Botulinum toxin treatments of neurological and neuropsychiatric disorders

ABSTRACT

Methods for preventing or treating neuropsychiatric disorder and/or a neurological disorder including a neurological disorder mediated by the thalamus. Neuropsychiatric disorders and/or a neurological disorders, including a thalamically mediated disorder can be treated by peripheral administration of a botulinum toxin to or to the vicinity of a trigeminal sensory nerve, thereby preventing or treating a neurological disorder and/or a neuropsychiatric disorder.

CROSS REFERENCE

This application is a divisional of U.S. application Ser. No.15/447,770, filed Mar. 2, 2017, now U.S. Pat. No. 10,064,921, which is acontinuation of U.S. application Ser. No. 14/247,469, filed Apr. 8,2014, now Abandoned, which is a continuation of U.S. application Ser.No. 10/964,898, filed Oct. 12, 2004, now U.S. Pat. No. 8,734,810, whichclaims the benefit of provisional application No. 60/574,957, filed May26, 2004, provisional application No. 60/556,150, filed Mar. 24, 2004and provisional application No. 60/515,362, filed Oct. 29, 2003,respectively, the entire contents of which applications are incorporatedherein by reference in their entireties.

BACKGROUND

The present invention is directed to medicaments and methods fortreating (including alleviating and/or preventing) neuropsychiatricand/or neurological disorders, including chronic neurological disorders,such as neurological disorders mediated by or influenced by thethalamus. In particular, the present invention is directed to amedicament containing a botulinum toxin for treating a neuropsychiatricand/or a chronic neurological disorder by administering the botulinumtoxin to a trigeminal nerve.

A neurological disorder is a central nervous system malfunction. Thecentral nervous system includes the brain. The brain includes the dorsalend of the spinal cord, medulla, brain stem, pons, cerebellum, cerebrumand cortex.

Epilepsy

Epilepsy describes a condition in which a person has recurrent seizuresdue to a chronic, underlying process. A seizure is a paroxysmal eventdue to abnormal, excessive, hypersynchronous discharges from anaggregate of central nervous system neurons. Among the many causes ofepilepsy, there are various epilepsy syndromes in which the clinical andpathologic characteristics are distinctive and suggest a specificunderlying etiology. The prevalence of epilepsy has been estimated at 5to 10 people per 1000 population. Severe, penetrating head trauma isassociated with up to a 50% risk of leading to epilepsy. Other causes ofepilepsy include stroke, infection and genetic susceptibility.

Antiepileptic drug therapy is the mainstay of treatment for mostpatients with epilepsy and a variety of drugs have been used. See e.g.,Fauci, A. S. et al., Harrison's Principles of Internal Medicine,McGraw-Hill, 14^(th) Edition (1998), page 2321. Twenty percent ofpatients with epilepsy are resistant to drug therapy despite efforts tofind an effective combination of antiepileptic drugs. Surgery can thenbe an option. Video-EEC monitoring can be used to define the anatomiclocation of the seizure focus and to correlate the abnormalelectrophysiologic activity with behavioral manifestations of theseizure. Routine scalp or scalp-sphenoidal recordings are usuallysufficient for localization. A high resolution MRI scan is routinelyused to identify structural lesions. Functional Imaging studies such asSPECT and PET are adjunctive tests that can help verify the localizationof an apparent epileptogenic region with an anatomic abnormality.

Once the presumed location of the seizure onset is identified,additional studies, including neuropsychological testing and theintracarotid amobarbital test (Wada's test) can be used to assesslanguage and memory localization and to determine the possiblefunctional consequences of surgical removal of the epileptogenic region.In some cases, the exact extent of the resection to be undertaken can bedetermined by performing cortical mapping at the time of the surgicalprocedure. This involves electrophysiologic recordings and corticalstimulation of the awake patient to identify the extent of epileptiformdisturbances and the function of the cortical regions in questions.

The most common surgical procedure for patients with temporal lobeepilepsy involves resection of the anteromedial temporal lobe (temporallobotomy) or a more limited removal of the underlying hippocampus andamygdala. Focal seizures arising from extratemporal regions may besuppressed by a focal neocortical resection. Unfortunately, about 5% ofpatients can still develop clinically significant complications fromsurgery and about 30% of patients treated with temporal lobectomy willstill have seizures.

Focal epilepsy can involve almost any part of the brain and usuallyresults from a localized lesion of functional abnormality. One type offocal epilepsy is the psychomotor seizure. Current therapy includes useof an EEG to localize abnormal spiking waves originating in areas oforganic brain disease that predispose to focal epileptic attacks,followed by surgical excision of the focus to prevent future attacks.

Chronic Pain

About one third of a population will experience chronic pain. In theUnited States chronic pain is the most common cause of long-termdisability, partially or totally disabling about fifty million people.As the population ages, the number of people needing treatment forchronic pain from back disorders, degenerative joint diseases,rheumatologic conditions, fibromyalgia, visceral diseases, and cancerscan be expected to increase.

Various events such as tissue injury can trigger pain signals to thebrain. These electrical impulses are carried by thin unmyelinated nervescalled nociceptors (C-fibers) that synapse with neurons in the dorsalhorn of the spinal cord. From the dorsal horn, the pain signal istransmitted via the spinothalamic tract to the cerebral cortex, where itis perceived, localized and interpreted.

Chronic pain is not just a prolonged version of acute pain. As painsignals are repeatedly generated, neural pathways undergo physiochemicalchanges that make the central nervous system hypersensitive to the painsignals and resistant to antinociceptive input. This is called centralsensitization.

Fibromyalgia is a chronic pain syndrome believed due to centralsensitization. Characteristic symptoms of fibromyalgia includewidespread pain, fatigue, sleep abnormalities and distress. Patientswith fibromyalgia show psychophysical evidence of hyperalgesia, that isa heightened response to mechanical, thermal and electrical stimuli atvarious tender or trigger points. In fibromyalgia the sensation at thesetender points is much more pronounced and patients have a decreasedthreshold of pain, responding to even minimal amounts of pressure. TheCopenhagen Fibromyalgia Symposium defined fibromyalgia as a situation inwhich a patient has at least 11 of 18 specified tender points, presentin all four quadrants of the body. Primary hyperalgesia develops in anarea where injury to tissues has occurred and secondary hyperalgesia maybe found in undamaged tissue. Peripheral and central abnormalities ofnociception have also been described in fibromyalgia. Importantnociceptor systems in the skin and muscles seem to undergo profoundchanges in patients with fibromyalgia through unknown mechanisms. Theyinclude sensitization of vanilloid receptor, acid-sensing ion channelreceptors and purino-receptors. Tissue mediators of inflammation andnerve growth factors can excite these receptors and cause extensivechanges in pain sensitivity, but patients with fibromyalgia lackconsistent evidence for inflammatory soft tissue abnormalities.Therefore, recent investigations have focused on central nervous systemmechanisms of pain in fibromyalgia. Treatments for fibromyalgia includesteroid trigger point injections and medications such as tricyclicantidepressants, neurontin, and narcotics, but these all have negativeside effects.

Post Stroke Pain

Pain can be debilitating and it is not uncommon to attribute widespreadpain in the elderly to osteoarthritis within the spinal columnstructures and peripheral joints or to other musculoskeletal conditions.However, if pain is widespread and exhibits neuropathic features, suchas dysaesthesias (poorly localized burning sensations that occur after astimulus is applied), allodynia (triggered by stimuli which are notnormally painful or pain which occurs other than in the areastimulated), hyperpathia (increased pain from normally painful stimuli)and hyperalgesia, it can be the result of a lesion or disorder such asThalamic Pain Syndrome or Central Post-Stroke Pain (CPSP) originatingfrom the central nervous system. The source of the pain is via thethalamus, the sensory processing center within the central nervoussystem.

A stroke is the result of loss of the blood supply to a part of thebrain and can result in weakness and slurred speech. CPSP develops inabout 8% of stroke patients, occurring within one to six months afterthe stroke. Common painkillers often have no effect on this pain,although some medications developed for epilepsy and depression mayreduce pain after strokes. CPSP has also been treated with intravenouslidocaine or oral opioids, as well as amitriptyline, carbamazepine,tegretol and lamotrigine, but these medications have adverse sideeffects.

Regional Pain Syndrome

Complex Regional Pain Syndrome (CRPS) (also called Reflex SympatheticDystrophy Syndrome) is a chronic condition characterized by severeburning pain, pathological changes in bone and skin, excessive sweating,tissue swelling, and extreme sensitivity to touch. The syndrome is anerve disorder that occurs at the site of an injury (most often to thearms or legs), and the disorder is unique in that it simultaneouslyaffects the nerves, skin, muscles, blood vessels, and bones. It occursespecially after injuries from high-velocity impacts such as those frombullets or shrapnel. However, it may occur without apparent injury. CRPSis believed to be the result of dysfunction in the central or peripheralnervous systems. CRPS I is frequently triggered by tissue injury; theterm describes all patients with the above symptoms but with nounderlying nerve injury. Patients with CRPS II experience the samesymptoms but their cases are clearly associated with a nerve injury.CRPS can strike at any age but is more common between the ages of 40 and60, although the number of CRPS cases among adolescents and young adultsis increasing. CRPS affects both men and women, although most expertsagree that it is more common in young women. One visible sign of CRPSnear the site of injury is warm, shiny red skin that later becomes cooland bluish.

The pain that patients report is out of proportion to the severity ofthe injury and gets worse, rather than better, over time. Eventually thejoints become stiff from disuse, and the skin, muscles, and boneatrophy. The symptoms of CRPS vary in severity and duration, and earlytreatment often results in remission. If treatment is delayed, however,the disorder can quickly spread to the entire limb, and changes in boneand muscle may become irreversible. In 50 percent of CRPS cases, painpersists longer than 6 months and sometimes for years. Physicians use avariety of drugs to treat CRPS. Elevation of the extremity and physicaltherapy are also used to treat CRPS. Injection of a local anesthetic isusually the first step in treatment. TENS (transcutaneous electricalstimulation), a procedure in which brief pulses of electricity areapplied to nerve endings under the skin, has helped some patients inrelieving chronic pain. In some cases, surgical or chemicalsympathectomy (interruption of the affected nerve(s) of the sympatheticnervous system) is performed to relieve pain, but these treatments mayalso destroy other sensations as well.

Phantom Limb Pain

Phantom limb pain is a conscious feeling of a painful limb, after thelimb has been amputated. The brain creates a “whole body map” whichremains intact even when a piece of the body no longer exists andphantom sensation or pain can result when the brain sends persistentmessages to limbs not there. Phantom pain or sensations can range intype and intensity. For example, a mild form might be experienced as asharp, intermittent stabbing pain causing the limb to jerk in reactionto the pain. An example of a more severe type might be the feeling thatthe missing limb is being crushed. Usually phantom limb pain diminishesin frequency and intensity over time. For a small number of amputees,however, phantom limb pain can become chronic and debilitating becauseof the frequency and severity of the pain. Anesthetics such aslidocaine, marcaine, novocaine, pontocaine, and xylocaine are often usedto prevent nerve cells from transmitting pain messages, thus relievingtrigger points and reducing stump pain, but their effects are temporary.Anti-inflammatories (acetaminophen, aspirin, ibuprofen), antidepressants(Amitriptyline, Elavil, Pamelor, Paxil, Prozac, Zoloft), anticonvulsants(Tegretol, Neurontin) and narcotics (Codeine, Demerol, Morphine,Percodan, Percocet) are other medications also used to treat phantompain, but these often have adverse side effects.

Demyelinating Disease Pain

Demyelinating diseases such as Multiple Sclerosis (MS), progressivemultifocal leukoencephalopathy (PML), disseminated necrotizingleukoencephalopathy (DNL), acute disseminated encephalomyelitis, andSchilder disease are acquired chronic, inflammatory diseases that resultin the destruction of myelin, the fatty insulation normally covering thenerve fibers that aids in the transmission of nerve impulses.Demyelination results in impaired transmission of action potentialsalong exposed axons, producing a multiplicity of neurological deficits,for example, sensory loss, weakness, visual loss, vertigo,incoordination, sphincter disturbances, and altered cognition. MS isusually characterized by a relapsing-remitting course in the earlystages, with full or nearly full recovery, initially. Over time thedisease enters an irreversible progressive phase of neurologicaldeficit. Acute relapses are caused by inflammatory demyelination, whiledisease progression is thought to result from axonal loss. The diseaseprocess affects myelinated fibre tracts, such as the optic nerves andthe white matter tracts of the brain and spinal cord. This may lead to avariety of symptoms, such as visual disturbances, bladder, bowel orsexual dysfunction, motor weakness and spasticity, sensory symptoms(numbness, dysaesthesia), cerebellar symptoms (tremor and ataxia), andother symptoms (fatigue, cognitive impairment and psychiatriccomplications). Therapies used to treat demyelinating disorders can becategorized into disease modifying therapies, drugs used in acuteexacerbations and drugs used to treat disease complications. So far, nodisease modifying therapy has been found that halts disease progressionor improves neurological status.

For this reason, the mainstay of treatment remains symptomaticmanagement. Current therapies predominantly influence the immune systemand target the inflammatory processes that are involved in the diseasepathology. Beta interferons (interferon beta-1b, known as Betaferon),glatiramer acetate (Copaxone) and mitoxantrone have been used for theirimmunomodulatory effects. These include inhibition of leukocyteproliferation and antigen presentation, inhibition of T-cell migrationacross the blood-brain barrier and modulation of cytokine production toproduce an anti-inflammatory environment. Oral steroids, such asprednisolone, may be effective in shortening acute attacks of MS. Otherpotential therapies are undergoing clinical evaluation, including T-cellvaccination, interleukin 10, matrix metalloproteinase inhibitors,plasmapheresis, vitamin D, retinoic acid, ganciclovir, valaciclovir,bone marrow transplantation and autologous stem cell transplantation.

As indicated, various therapeutic treatments are available to astreatments for various neurological disorders, such as thalamicallymediated disorders. However, these therapeutic treatments have severaladverse side-effects. These side-effects may be attributed to the factthat the pharmaceutical agents are typically administered systemically,and therefore, the agents have a relatively non-specific action withrespect to the various biological systems of the patient. For example,administration of benzodiazepines may result in sedation and musclerelaxation. In addition, tolerance may develop to these drugs, as wellas withdrawal seizures may develop. Current therapeutic strategies alsorequire consistent and repeated administration of the agents to achievethe desired effects.

Neuropsychiatric Disorders

A neuropsychiatric disorder is a neurological disturbance that istypically labeled according to which of the four mental faculties isaffected. For example, one group of neuropsychiatric disorders includesdisorders of thinking and cognition, such as schizophrenia and delirium.A second group of neuropsychiatric disorders includes disorders of mood,such as affective disorders and anxiety. A third group ofneuropsychiatric disorders includes disorders of social behavior, suchas character defects and personality disorders. And a fourth group ofneuropsychiatric disorders includes disorders of learning, memory, andintelligence, such as mental retardation and dementia. Accordingly,neuropsychiatric disorders encompass schizophrenia, delirium,Alzheimer's disease, depression, mania, attention deficit disorders,drug addiction, dementia, agitation, apathy, anxiety, psychoses,personality disorders, bipolar disorders, obsessive-compulsivedisorders, eating disorders, post-traumatic stress disorders,irritability, and disinhibition.

Schizophrenia

Schizophrenia is a disorder that affects about one percent of the worldpopulation. Three general symptoms of schizophrenia are often referredto as positive symptoms, negative symptoms, and disorganized symptoms.Positive symptoms can include delusions (abnormal beliefs),hallucinations (abnormal perceptions), and disorganized thinking. Thehallucinations of schizophrenia can be auditory, visual, olfactory, ortactile. Disorganized thinking can manifest itself in schizophrenicpatients by disjointed speech and the inability to maintain logicalthought processes. Negative symptoms can represent the absence of normalbehavior. Negative symptoms include emotional flatness or lack ofexpression and can be characterized by social withdrawal, reducedenergy, reduced motivation, and reduced activity. Catatonia can also beassociated with negative symptoms of schizophrenia. The symptoms ofschizophrenia should continuously persist for a duration of about sixmonths in order for the patient to be diagnosed as schizophrenic. Basedon the types of symptoms a patient reveals, schizophrenia can becategorized into subtypes including catatonic schizophrenia, paranoidschizophrenia, and disorganized schizophrenia.

The brains of schizophrenic patients are often characterized by enlargedlateral ventricles, which can be associated with a reduction of thehippocampus and an enhancement in the size of the basal ganglia.Schizophrenic patients can also have enlarged third ventricles andwidening of sulci. These anatomical characterizations point to areduction in cortical tissue.

Although the cause of schizophrenia is not precisely known, there areseveral hypotheses. One hypothesis is that schizophrenia is associatedwith increased dopamine activity within the cortical and limbic areas ofthe brain. This hypothesis is supported by the therapeutic effectsachieved by antipsychotic drugs that block certain dopamine receptors.In addition, amphetamine use can be associated with schizophrenia-likepsychotic symptoms, and it is known that amphetamines act on dopaminereceptors.

Examples of antipsychotic drugs that may be used to treat schizophrenicpatients include phenothiazines, such as chlorpromazine andtriflupromazine; thioxanthenes, such as chlorprothixene; fluphenazine;butyrophenones, such as haloperidol; loxapine; mesoridazine; molindone;quetiapine; thiothixene; trifluoperazine; perphenazine; thioridazine;risperidone; dibenzodiazepines, such as clozapine; and olanzapine.Although these agents may relieve the symptoms of schizophrenia, theiradministration can result in undesirable side effects includingParkinson's disease-like symptoms (tremor, muscle rigidity, loss offacial expression); dystonia; restlessness; tardive dyskinesia; weightgain; skin problems; dry mouth; constipation; blurred vision;drowsiness; slurred speech and agranulocytosis.

Antipsychotic drugs are believed to primarily act on dopamine receptorswith a particular affinity for the D₂, D₃, and D₄ receptors. It isbelieved that the D₃ and D₄ receptors may have a higher affinity forcertain antipsychotics, such as clozapine, as compared to the others.The brains of schizophrenic patients appear to have increased numbers ofD₂ receptors in the caudate nucleus, the nucleus accumbens (ventralstriatum), and the olfactory tubercle.

Dopamine neurons may be organized into four major subsystems: thetuberoinfundibular system; the nigrostriatal system; the mesolimbicsystem; and the mesocortical system. The tuberoinfundibular dopaminergicsystem originates in cell bodies of the arcuate nucleus of thehypothalamus and projects to the pituitary stalk. This system may beinvolved in secondary neuroendocrine abnormalities in schizophrenia. Thenigrostriatal dopaminergic system originates in the substantia nigra andprojects primarily to the putamen and the caudate nucleus. Themesolimbic dopaminergic system originates in the ventral tegmental areaand projects to the mesial component of the limbic system, whichincludes the nucleus accumbens, the nuclei of the stria terminalis,parts of the amygdala and hippocampus, the lateral septal nuclei, andthe mesial frontal, anterior cingulate, and entorhinal cortex. Thenucleus accumbens is a convergence site from the amygdala, hippocampus,entorhinal area, anterior cingulate area, and parts of the temporallobe. Thus, the mesolimbic dopaminergic projection can modulate andtransform information conveyed from the nucleus accumbens to the septum,hypothalamus, anterior cingulate area, and frontal lobes, and overactivemodulation of the nucleus accumbens output to these areas can contributeto positive symptoms associated with schizophrenia. The mesocorticaldopaminergic system originates in the ventral tegmental area andprojects to the neocortex and heavily to the prefrontal cortex. Thiscomponent may be important in the negative symptoms of schizophrenia.

The ventral tegmental area, which is the source of origination of thedopaminergic input to the nucleus accumbens, receives a cholinergicinput from the pedunculopontine nuclei of the brainstem. Thepedunculopontine nucleus provides an excitatory cholinergic input to theventral tegmental area (Clarke et al., Innervation of substantia nigraneurons by cholinergic afferents from the pedunculopontine nucleus inthe rat. Neuroanatomical and electrophysiological evidence,Neuroscience, 23:1011-1019, 1987). It has been reported thatschizophrenic patients have an increased number of cholinergic neuronsin the pedunculopontine nuclei (Garcia-Rill et al., Mesopontine neuronsin schizophrenia, Neuroscience, 66(2):321-335, 1995). However, theseresults were not confirmed in one study (German et al., Mesopontinecholinergic and non-cholinergic neurons in schizophrenia, Neuroscience,94(1):33-38, 1999).

Mania

Mania is a sustained form of euphoria that affects millions of people inthe United States who suffer from depression. Manic episodes can becharacterized by an elevated, expansive, or irritable mood lastingseveral days, and is often accompanied by other symptoms, such as,overactivity, overtalkativeness, social intrusiveness, increased energy,pressure of ideas, grandiosity, distractibility, decreased need forsleep, and recklessness. Manic patients can also experience delusionsand hallucinations.

Depressive disorders can involve serotonergic and noradrenergic neuronalsystems based on current therapeutic regimes that target serotonin andnoradrenalin receptors. Serotonergic pathways originate from the raphenuclei of the brain stem, and noradrenergic pathways originate from thelocus coeruleus. Decreasing the electrical activity of neurons in thelocus coeruleus can be associated with the effects mediated bydepression medications.

Mania may results from an imbalance in certain chemical messengerswithin the brain. It has been proposed that mania is attributed to adecline in acetylcholine. A decline in acetylcholine may result in arelatively greater level of norepinephrine. Administering phosphatidylcholine has been reported to alleviate the symptoms of mania.

Anxiety

Anxiety disorders may affect between approximately ten to thirty percentof the population, and can be characterized by frequent occurrence ofsymptoms of fear including arousal, restlessness, heightenedresponsiveness, sweating, racing heart, increased blood pressure, drymouth, a desire to run or escape, and avoidance behavior. Generalizedanxiety persists for several months, and is associated with motortension (trembling, twitching, muscle aches, restlessness); autonomichyperactivity (shortness of breath, palpitations, increased heart rate,sweating, cold hands), and vigilance and scanning (feeling on edge,exaggerated startle response, difficult in concentrating).

Benzodiazepines, which enhance the inhibitory effects of the gammaaminobutyric acid (GABA) type A receptor, are frequently used to treatanxiety. Buspirone is another effective anxiety treatment.

Alzheimer's Disease

Alzheimer's disease is a degenerative brain disorder characterized bycognitive and noncognitive neuropsychiatric symptoms, which accounts forapproximately 60% of all cases of dementia for patients over 65 yearsold. Psychiatric symptoms are common in Alzheimer's disease, withpsychosis (hallucinations and delusions) present in approximately fiftypercent of affected patients. Similar to schizophrenia, positivepsychotic symptoms are common in Alzheimer's disease. Delusionstypically occur more frequently than hallucinations. Alzheimer'spatients may also exhibit negative symptoms, such as disengagement,apathy, diminished emotional responsiveness, loss of volition, anddecreased initiative.

Alzheimer's disease patients may also exhibit enlargement of bothlateral and third ventricles as well as atrophy of temporal structures.

It is possible that the psychotic symptoms of Alzheimer's diseaseinvolve a shift in the concentration of dopamine or acetylcholine, whichmay augment a dopaminergic/cholinergic balance, thereby resulting inpsychotic behavior. For example, it has been proposed that an increaseddopamine release may be responsible for the positive symptoms ofschizophrenia. This may result in a positive disruption of thedopaminergic/cholinergic balance. In Alzheimer's disease, the reductionin cholinergic neurons effectively reduces acetylcholine releaseresulting in a negative disruption of the dopaminergic/cholinergicbalance. Indeed, antipsychotic agents that are used to relieve psychosisof schizophrenia are also useful in alleviating psychosis in Alzheimer'spatients.

Several of the symptoms associated with neuropsychiatric disordersappear to be, at least in part, attributed to hyperexcitability (i.e.sensitization to afferent input from peripheral nerves) of neuronswithin the brain. This interpretation is supported by the pharmacologyassociated with current therapeutic treatments. For example, many of theantipsychotic treatments are directed to interfering with binding ofdopamine to dopamine receptors, as discussed above. Similarly, mania andanxiety are often treated with benzodiazepines, which enhance theinhibitory effects of GABA-mediated inhibition. U.S. Pat. No. 6,306,403discloses intracranial administration of a botulinum toxin to treatvarious movement disorders. Additionally, it is known that stereotacticprocedures can be used to administer a pharmaceutical to a discretebrain area to successfully alleviate a parkinsonian tremor. See e.g.Pahapill P. A., et al., Tremor arrest with thalamic microinjections ofmuscimol in patients with essential tremor, Ann Neur 46(2); 249-252(1999).

However, current therapeutic treatments result in several adverseside-effects. These side-effects may be attributed to the fact that thepharmaceutical agents are typically administered systemically, andtherefore, the agents have a relatively non-specific action with respectto the various biological systems of the patient. For example,administration of benzodiazepines may result in sedation and musclerelaxation. In addition, tolerance may develop to these drugs, as wellas withdrawal seizures may develop. Current therapeutic strategies alsorequire consistent and repeated administration of the agents to achievethe desired effects.

Trigeminal Nerve

The trigeminal nerve has three major branches, a number of smallerbranches and is the great sensory nerve of the head and neck, carryingtouch, temperature, pain, and proprioception (position sense) signalsfrom the face and scalp to the brainstem. Trigeminal sensory fibersoriginate in the skin, course toward the trigeminal ganglion (a sensorynerve cell body), pass through the trigeminal ganglion, and travelwithin the trigeminal nerve to the sensory nucleus of the trigeminalnerve located in the brainstem.

The three major branches of the trigeminal nerve are the ophthalmic (V₁,sensory), maxillary (V₂, sensory) and mandibular (V₃, motor and sensory)branches. The large trigeminal sensory root and smaller trigeminal motorroot leave the brainstem at the midlateral surface of pons. The sensoryroot terminates in the largest of the cranial nerve nuclei which extendsfrom the pons all the way down into the second cervical level of thespinal cord. The sensory root joins the trigeminal or semilunar ganglionbetween the layers of the dura mater in a depression on the floor of themiddle crania fossa. The trigeminal motor root originates from cellslocated in the masticator motor nucleus of trigeminal nerve located inthe midpons of the brainstem. The motor root passes through thetrigeminal ganglion and combines with the corresponding sensory root tobecome the mandibular nerve. It is distributed to the muscles ofmastication, the mylohyoid muscle and the anterior belly of thedigastric. The three sensory branches of the trigeminal nerve emanatefrom the ganglia to form the three branches of the trigeminal nerve. Theophthalmic and maxillary branches travel in the wall of the cavernoussinus just prior to leaving the cranium. The ophthalmic branch travelsthrough the superior orbital fissure and passes through the orbit toreach the skin of the forehead and top of the head. The maxillary nerveenters the cranium through the foramen rotundum via the pterygopalatinefossa. Its sensory branches reach the pterygopalatine fossa via theinferior orbital fissure (face, cheek and upper teeth) andpterygopalatine canal (soft and hard palate, nasal cavity and pharynx).There are also meningeal sensory branches that enter the trigeminalganglion within the cranium. The sensory part of the mandibular nerve iscomposed of branches that carry general sensory information from themucous membranes of the mouth and cheek, anterior two-thirds of thetongue, lower teeth, skin of the lower jaw, side of the head and scalpand meninges of the anterior and middle cranial fossae.

The sensory nuclei of the trigeminal nerve are located within thebrainstem, in the dorsolateral pons. The mesencephalic tract and themotor nucleus of the trigeminal nerve lie more medially. The superiorcerebellar peduncle lies posteriorly. It is continuous inferiorly withthe spinal nucleus of the trigeminal nerve that extends into themedulla. Superiorly, the sensory nuclei on each side are continuous withthe mesencephalic nucleus.

Importantly, the sensory nuclei of the trigeminal nerve receive afferent(sensory input) fibres from: (1) the trigeminal nerve ophthalmicdivision (e.g. general sensation from supraorbital area, cornea, iris,ethmoid sinuses), (2) trigeminal nerve maxillary division (e.g.sensation from temple, cheek, oral cavity, upper pharynx), and (3)trigeminal nerve mandibular division (e.g. sensation from middle cranialfossa, inner cheek, anterior two thirds of the tongue, chin), (4) facialnerve (e.g. general sensation from external auditory meatus), (5)glossopharyngeal nerve (e.g. general sensation from middle ear, tonsils,oropharynx, posterior one third of the tongue), (6) vagus nerve(auricular, meningeal, internal laryngeal and recurrent laryngealbranches).

Thus, primary neurons in the trigeminal ganglion synapse on the mainsensory trigeminal nucleus and on the spinal trigeminal nucleus in thebrainstem. The spinal nucleus of the trigeminal system extends to theupper cervical spine, where connections with cervical dermatomes exist.These dermatomes are innervated by the cervical plexus, which hassensory branches from C1 to C4. The trigeminal nerve also innervatesstretch receptors in the muscles of mastication. The cell bodies ofthese neurons are in the mesencephalic trigeminal nucleus in themidbrain and pons).

As indicated by FIG. 1, the ascending (afferent) second order trigeminalneurons from the main sensory trigeminal nucleus, and the ascendingsecond order neurons from the spinal trigeminal nucleus ascend andsynapse in the thalamus. Projections from the thalamus are to the facialrepresentation of the sensory cortex. Central projections from themesencephalic trigeminal nucleus are to the motor cortex. Thalamicprojections to the sensory cortex follow a somatotopic organization. Thehand and face have disproportionately greater representation on ahomunculus map. This body map is not static, but dynamically controlledby the pattern of use, with increased use leading to increased corticalrepresentation. Notably, the primary somatosensory cortex in the postcentral gyrus, receives input from the thalamus, and projects to thesecondary somatic sensory cortex in the parietal operculum. There arealso efferent connections from the sensory cortex to the motor cortex.Notably, the trigeminal nerve is a very large nerve and 28% of thesensory cortex is devoted to it alone.

Botulinum Toxin

The genus Clostridium has more than one hundred and twenty sevenspecies, grouped according to their morphology and functions. Theanaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum toxin, which causes aneuroparalytic illness in humans and animals referred to as botulism.The spores of Clostridium botulinum are found in soil and can grow inimproperly sterilized and sealed food containers of home basedcanneries, which are the cause of many of the cases of botulism. Theeffects of botulism typically appear 18 to 36 hours after eating thefoodstuffs infected with a Clostridium botulinum culture or spores. Thebotulinum toxin can apparently pass unattenuated through the lining ofthe gut and shows a high affinity for cholinergic motor neurons.Symptoms of botulinum toxin intoxication can progress from difficultywalking, swallowing and speaking to paralysis of the respiratory musclesand death.

Botulinum toxin type A is the most lethal natural biological agent knownto man. About 50 picograms of a commercially available botulinum toxintype A (purified neurotoxin complex, Available from Allergan, Inc., ofIrvine, Calif. under the tradename BOTOX® in 100 unit vials) is a LD50in mice (i.e. 1 unit). One unit of BOTOX® contains about 50 picograms(about 56 attomoles) of botulinum toxin type A complex. Interestingly,on a molar basis, botulinum toxin type A is about 1.8 billion times morelethal than diphtheria, about 600 million times more lethal than sodiumcyanide, about 30 million times more lethal than cobra toxin and about12 million times more lethal than cholera. Singh, Critical Aspects ofBacterial Protein Toxins, pages 63-84 (chapter 4) of Natural Toxins II,edited by B. R. Singh et al., Plenum Press, New York (1976) (where thestated LD50 of botulinum toxin type A of 0.3 ng equals 1 U is correctedfor the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U)of botulinum toxin is defined as the LD50 upon intraperitoneal injectioninto female Swiss Webster mice weighing 18 to 20 grams each.

Seven generally immunologically distinct botulinum toxins have beencharacterized, these being respectively botulinum toxin serotypes A, B,C₁, D, E, F and G each of which is distinguished by neutralization withtype-specific antibodies. The different serotypes of botulinum toxinvary in the animal species that they affect and in the severity andduration of the paralysis they evoke. For example, it has beendetermined that botulinum toxin type A is 500 times more potent, asmeasured by the rate of paralysis produced in the rat, than is botulinumtoxin type B. Additionally, botulinum toxin type B has been determinedto be non-toxic in primates at a dose of 480 U/kg which is about 12times the primate LD50 for botulinum toxin type A. Moyer E et al.,Botulinum Toxin Type B: Experimental and Clinical Experience, beingchapter 6, pages 71-85 of “Therapy With Botulinum Toxin”, edited byJankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxinapparently binds with high affinity to cholinergic motor neurons, istranslocated into the neuron and blocks the release of acetylcholine.Additional uptake can take place through low affinity receptors, as wellas by phagocytosis and pinocytosis.

Regardless of serotype, the molecular mechanism of toxin intoxicationappears to be similar and to involve at least three steps or stages. Inthe first step of the process, the toxin binds to the presynapticmembrane of the target neuron through a specific interaction between theheavy chain (the H chain or HC), and a cell surface receptor. Thereceptor is thought to be different for each type of botulinum toxin andfor tetanus toxin. The carboxyl end segment of the HC appears to beimportant for targeting of the botulinum toxin to the cell surface.

In the second step, the botulinum toxin crosses the plasma membrane ofthe target cell. The botulinum toxin is first engulfed by the cellthrough receptor-mediated endocytosis, and an endosome containing thebotulinum toxin is formed. The toxin then escapes the endosome into thecytoplasm of the cell. This step is thought to be mediated by the aminoend segment of the HO, the HN, which triggers a conformational change ofthe toxin in response to a pH of about 5.5 or lower. Endosomes are knownto possess a proton pump which decreases intra-endosomal pH. Theconformational shift exposes hydrophobic residues in the toxin, whichpermits the botulinum toxin to embed itself in the endosomal membrane.The botulinum toxin (or at least the light chain of the botulinum) thentranslocates through the endosomal membrane into the cytoplasm.

The last step of the mechanism of botulinum toxin activity appears toinvolve reduction of the disulfide bond joining the heavy chain, Hchain, and the light chain, L chain. The entire toxic activity ofbotulinum and tetanus toxins is contained in the L chain of theholotoxin; the L chain is a zinc (Zn++) endopeptidase which selectivelycleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin types B, D, F and G causedegradation of synaptobrevin (also called vesicle-associated membraneprotein (VAMP)), a synaptosomal membrane protein. Most of the VAMPpresent at the cytoplasmic surface of the synaptic vesicle is removed asa result of any one of these cleavage events. Botulinum toxin serotype Aand E cleave SNAP-25. Botulinum toxin serotype C1 was originally thoughtto cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Eachof the botulinum toxins specifically cleaves a different bond, exceptbotulinum toxin type B (and tetanus toxin) which cleave the same bond.Each of these cleavages block the process of vesicle-membrane docking,thereby preventing exocytosis of vesicle content.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletal muscles(i.e. motor disorders). In 1989, a botulinum toxin type A complex wasapproved by the U.S. Food and Drug Administration for the treatment ofblepharospasm, strabismus and hemifacial spasm. Subsequently, abotulinum toxin type A was also approved by the FDA for the treatment ofcervical dystonia and for the treatment of glabellar lines, and abotulinum toxin type B was approved for the treatment of cervicaldystonia. Non-type A botulinum toxin serotypes apparently have a lowerpotency and/or a shorter duration of activity as compared to botulinumtoxin type A. Clinical effects of peripheral intramuscular botulinumtoxin type A are usually seen within one week of injection. The typicalduration of symptomatic relief from a single intramuscular injection ofbotulinum toxin type A averages about three months, althoughsignificantly longer periods of therapeutic activity have been reported.

Although all the botulinum toxins serotypes apparently inhibit releaseof the neurotransmitter acetylcholine at the neuromuscular junction,they do so by affecting different neurosecretory proteins and/orcleaving these proteins at different sites. For example, botulinum typesA and E both cleave the 25 kiloDalton (kD) synaptosomal associatedprotein (SNAP-25), but they target different amino acid sequences withinthis protein. Botulinum toxin types B, D, F and G act onvesicle-associated protein (VAMP, also called synaptobrevin), with eachserotype cleaving the protein at a different site. Finally, botulinumtoxin type C1 has been shown to cleave both syntaxin and SNAP-25. Thesedifferences in mechanism of action may affect the relative potencyand/or duration of action of the various botulinum toxin serotypes.Apparently, a substrate for a botulinum toxin can be found in a varietyof different cell types. See e.g. Biochem J 1; 339 (pt 1):159-65:1999,and Mov Disord, 10(3):376:1995 (pancreatic islet B cells contains atleast SNAP-25 and synaptobrevin).

The molecular weight of the botulinum toxin protein molecule, for allseven of the known botulinum toxin serotypes, is about 150 kD.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900 kD,500 kD and 300 kD forms. Botulinum toxin types B and C1 is apparentlyproduced as only a 700 kD or 500 kD complex. Botulinum toxin type D isproduced as both 300 kD and 500 kD complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kD complexes. Thecomplexes (i.e. molecular weight greater than about 150 kD) are believedto contain a non-toxin hemagglutinin proteins and a non-toxin andnon-toxic nonhemagglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule comprise the relevant neurotoxincomplex) may act to provide stability against denaturation to thebotulinum toxin molecule and protection against digestive acids when abotulinum toxin is ingested. Additionally, it is possible that thelarger (greater than about 150 kD molecular weight) botulinum toxincomplexes may result in a slower rate of diffusion of the botulinumtoxin away from a site of intramuscular injection of a botulinum toxincomplex.

In vitro studies have indicated that botulinum toxin inhibits potassiumcation induced release of both acetylcholine and norepinephrine fromprimary cell cultures of brainstem tissue. Additionally, it has beenreported that botulinum toxin inhibits the evoked release of bothglycine and glutamate in primary cultures of spinal cord neurons andthat in brain synaptosome preparations botulinum toxin inhibits therelease of each of the neurotransmitters acetylcholine, dopamine,norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A andC Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, JNeurochem 51(2); 522-527:1988) CGRP, substance P and glutamate(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks GlutamateExocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.Biochem 165; 675-681:1897. Thus, when adequate concentrations are used,stimulus-evoked release of most neurotransmitters can be blocked bybotulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterizationof Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373-1412 at 1393; Bigalke H., et al., Botulinum A Neurotoxin InhibitsNon-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons inCulture, Brain Research 360; 318-324:1985; Habermann E., Inhibition byTetanus and Botulinum A Toxin of the release of [3H]Noradrenaline and[3H]GABA From Rat Brain Homogenate, Experientia 44; 224-226:1988,Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Releaseand Uptake of Various Transmitters, as Studied with ParticulatePreparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's ArchPharmacol 316; 244-251:1981, and; Jankovic J. et al., Therapy WithBotulinum Toxin, Marcel Dekker, Inc., (1994), page 5.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures. Allthe botulinum toxin serotypes are initially synthesized as inactivesingle chain proteins which must be cleaved or nicked by proteases tobecome neuroactive. The bacterial strains that make botulinum toxinserotypes A and G possess endogenous proteases and serotypes A and G cantherefore be recovered from bacterial cultures in predominantly theiractive form. In contrast, botulinum toxin serotypes C1, D and E aresynthesized by nonproteolytic strains and are therefore typicallyunactivated when recovered from culture. Serotypes B and F are producedby both proteolytic and nonproteolytic strains and therefore can berecovered in either the active or inactive form. However, even theproteolytic strains that produce, for example, the botulinum toxin typeB serotype only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin is likely to be inactive, possibly accounting for the knownsignificantly lower potency of botulinum toxin type B as compared tobotulinum toxin type A. The presence of inactive botulinum toxinmolecules in a clinical preparation will contribute to the overallprotein load of the preparation, which has been linked to increasedantigenicity, without contributing to its clinical efficacy.Additionally, it is known that botulinum toxin type B has, uponintramuscular injection, a shorter duration of activity and is also lesspotent than botulinum toxin type A at the same dose level.

High quality crystalline botulinum toxin type A can be produced from theHall A strain of Clostridium botulinum with characteristics of ≥3×107U/mg, an A260/A278 of less than 0.60 and a distinct pattern of bandingon gel electrophoresis. The known Shantz process can be used to obtaincrystalline botulinum toxin type A, as set forth in Shantz, E. J., etal, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56; 80-99:1992. Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. The known process can also be used, upon separation outof the non-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDmolecular weight with a specific potency of 1-2×108 LD50 U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDmolecular weight with a specific potency of 1-2×108 LD50 U/mg orgreater, and; purified botulinum toxin type F with an approximately 155kD molecular weight with a specific potency of 1-2×107 LD50 U/mg orgreater.

Botulinum toxins and/or botulinum toxin complexes can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals ofSt Louis, Mo. Pure botulinum toxin can also be used to prepare apharmaceutical composition.

As with enzymes generally, the biological activities of the botulinumtoxins (which are intracellular peptidases) is dependant, at least inpart, upon their three dimensional conformation. Thus, botulinum toxintype A is detoxified by heat, various chemicals surface stretching andsurface drying. Additionally, it is known that dilution of a botulinumtoxin complex obtained by the known culturing, fermentation andpurification to the much, much lower toxin concentrations used forpharmaceutical composition formulation results in rapid detoxificationof the toxin unless a suitable stabilizing agent is present. Dilution ofthe toxin from milligram quantities to a solution containing nanogramsper milliliter presents significant difficulties because of the rapidloss of specific toxicity upon such great dilution. Since the botulinumtoxin may be used months or years after the toxin containingpharmaceutical composition is formulated, the toxin can be stabilizedwith a stabilizing agent such as albumin and gelatin.

A commercially available botulinum toxin containing pharmaceuticalcomposition is sold under the trademark BOTOX® (available from Allergan,Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxintype A complex, albumin and sodium chloride packaged in sterile,vacuum-dried form. The botulinum toxin type A is made from a culture ofthe Hall strain of Clostridium botulinum grown in a medium containingN—Z amine and yeast extract. The botulinum toxin type A complex ispurified from the culture solution by a series of acid precipitations toa crystalline complex consisting of the active high molecular weighttoxin protein and an associated hemagglutinin protein. The crystallinecomplex is re-dissolved in a solution containing saline and albumin andsterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-driedproduct is stored in a freezer at or below −5° C. BOTOX® can bereconstituted with sterile, non-preserved saline prior to intramuscularinjection. Each vial of BOTOX® contains about 100 units (U) ofClostridium botulinum toxin type A purified neurotoxin complex, 0.5milligrams of human serum albumin and 0.9 milligrams of sodium chloridein a sterile, vacuum-dried form without a preservative.

To reconstitute vacuum-dried BOTOX®, sterile normal saline without apreservative; (0.9% Sodium Chloride Injection) is used by drawing up theproper amount of diluent in the appropriate size syringe. Since BOTOX®may be denatured by bubbling or similar violent agitation, the diluentis gently injected into the vial. For sterility reasons BOTOX® ispreferably administered within four hours after the vial is removed fromthe freezer and reconstituted. During these four hours, reconstitutedBOTOX® can be stored in a refrigerator at about 2° C. to about 8° C.Reconstituted, refrigerated BOTOX® has been reported to retain itspotency for at least about two weeks. Neurology, 48:249-53:1997.

It has been reported that botulinum toxin type A has been used inclinical settings as follows:

(1) about 75-125 units of BOTOX® per intramuscular injection (multiplemuscles) to treat cervical dystonia;(2) 5-10 units of BOTOX® per intramuscular injection to treat glabellarlines (brow furrows) (5 units injected intramuscularly into the procerusmuscle and 10 units injected intramuscularly into each corrugatorsupercilii muscle);(3) about 30-80 units of BOTOX® to treat constipation by intrasphincterinjection of the puborectalis muscle;(4) about 1-5 units per muscle of intramuscularly injected BOTOX® totreat blepharospasm by injecting the lateral pre-tarsal orbicularisoculi muscle of the upper lid and the lateral pre-tarsal orbicularisoculi of the lower lid.(5) to treat strabismus, extraocular muscles have been injectedintramuscularly with between about 1-5 units of BOTOX®, the amountinjected varying based upon both the size of the muscle to be injectedand the extent of muscle paralysis desired (i.e. amount of dioptercorrection desired).(6) to treat upper limb spasticity following stroke by intramuscularinjections of BOTOX® into five different upper limb flexor muscles, asfollows:(a) flexor digitorum profundus: 7.5 U to 30 U(b) flexor digitorum sublimis: 7.5 U to 30 U(c) flexor carpi ulnaris: 10 U to 40 U(d) flexor carpi radialis: 15 U to 60 U(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscleshas been injected at the same treatment session, so that the patientreceives from 90 U to 360 U of upper limb flexor muscle BOTOX® byintramuscular injection at each treatment session.(7) to treat migraine, pericranial injected (injected symmetrically intoglabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX®has showed significant benefit as a prophylactic treatment of migrainecompared to vehicle as measured by decreased measures of migrainefrequency, maximal severity, associated vomiting and acute medicationuse over the three month period following the 25 U injection.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J. Neurology 6 (Suppl 4): S111-S1150:1999), and insome circumstances for as long as 27 months, when used to treat glands,such as in the treatment of hyperhidrosis. See e.g. Bushara K.,Botulinum toxin and rhinorrhea, Otolaryngol Head Neck Surg 1996;114(3):507, and The Laryngoscope 109:1344-1346:1999. However, the usualduration of an intramuscular injection of Botox® is typically about 3 to4 months.

The success of botulinum toxin type A to treat a variety of clinicalconditions has led to interest in other botulinum toxin serotypes. Twocommercially available botulinum type A preparations for use in humansare BOTOX® available from Allergan, Inc., of Irvine, Calif., andDysport® available from Beaufour Ipsen, Porton Down, England. Abotulinum toxin type B preparation (MyoBloc®) is available from ElanPharmaceuticals of San Francisco, Calif.

In addition to having pharmacologic actions at the peripheral location,botulinum toxins may also have inhibitory effects in the central nervoussystem. Work by Weigand et al, Naunyn-Schmiedeberg's Arch. Pharmacol.1976; 292, 161-165, and Habermann, Naunyn-Schmiedeberg's Arch.Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able toascend to the spinal area by retrograde transport. As such, a botulinumtoxin injected at a peripheral location, for example intramuscularly,may be retrograde transported to the spinal cord.

U.S. Pat. No. 5,989,545 discloses that a modified clostridial neurotoxinor fragment thereof, preferably a botulinum toxin, chemically conjugatedor recombinantly fused to a particular targeting moiety can be used totreat pain by administration of the agent to the spinal cord.

It has been reported that use of a botulinum toxin to treat variousspasmodic muscle conditions can result in reduced depression andanxiety, as the muscle spasm is reduced. Murry T., et al., Spasmodicdysphonia; emotional status and botulinum toxin treatment, ArchOtolaryngol 1994 March; 120(3): 310-316; Jahanshahi M., et al.,Psychological functioning before and after treatment of torticollis withbotulinum toxin, J Neurol Neurosurg Psychiatry 1992; 55(3): 229-231.Additionally, German patent application DE 101 50 415 A1 discussesintramuscular injection of a botulinum toxin to treat depression andrelated affective disorders.

A botulinum toxin has also been proposed for or has been used to treatskin wounds (U.S. Pat. No. 6,447,787), various autonomic nervedysfunctions (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat. No.6,458,365), migraine headache pain (U.S. Pat. No. 5,714,468), sinusheadache (U.S. patent application Ser. No. 429,069), post-operative painand visceral pain (U.S. Pat. No. 6,464,986), neuralgia pain (U.S. patentapplication Ser. No. 630,587), hair growth and hair retention (U.S. Pat.No. 6,299,893), dental related ailments (U.S. provisional patentapplication Ser. No. 60/418,789), fibromyalgia (U.S. Pat. No.6,623,742), various skin disorders (U.S. patent application Ser. No.10/731,973), motion sickness (U.S. patent application Ser. No. 752,869),psoriasis and dermatitis (U.S. Pat. No. 5,670,484), injured muscles(U.S. Pat. No. 6,423,319) various cancers (U.S. Pat. No. 6,139,845),smooth muscle disorders (U.S. Pat. No. 5,437,291), down turned mouthcorners (U.S. Pat. No. 6,358,917), nerve entrapment syndromes (U.S.patent application 2003 0224019), various impulse disorders (U.S. patentapplication Ser. No. 423,380), acne (WO 03/011333) and neurogenicinflammation (U.S. Pat. No. 6,063,768). Controlled release toxinimplants are known (see e.g. U.S. Pat. Nos. 6,306,423 and 6,312,708) asis transdermal botulinum toxin administration (U.S. patent applicationSer. No. 10/194,805).

Botulinum toxin type A has been used to treat epilepsia partialiscontinua, a type of focal motor epilepsy. Bhattacharya K., et al., Noveluses of botulinum toxin type A: two case reports, Mov Disord 2000;15(Suppl 2):51-52.

It is known that a botulinum toxin can be used to: weaken the chewing orbiting muscle of the mouth so that self inflicted wounds and resultingulcers can heal (Payne M., et al, Botulinum toxin as a novel treatmentfor self mutilation in Lesch-Nyhan syndrome, Ann Neurol 2002 September;52(3 Supp 1):5157); permit healing of benign cystic lesions or tumors(Blugerman G., et al., Multiple eccrine hidrocystomas: A new therapeuticoption with botulinum toxin, Dermatol Surg 2003 May; 29(5):557-9); treatanal fissure (Jost W., Ten years' experience with botulinum toxin inanal fissure, Int J Colorectal Dis 2002 September; 17(5):298-302, and;treat certain types of atopic dermatitis (Heckmann M., et al., Botulinumtoxin type A injection in the treatment of lichen simplex: An open pilotstudy, J Am Acad Dermatol 2002 April; 46(4):617-9).

Additionally, a botulinum toxin may have an effect to reduce inducedinflammatory pain in a rat formalin model. Aoki K., et al, Mechanisms ofthe antinociceptive effect of subcutaneous Botox: Inhibition ofperipheral and central nociceptive processing, Cephalalgia 2003September; 23(7):649. Furthermore, it has been reported that botulinumtoxin nerve blockage can cause a reduction of epidermal thickness. Li Y,et al., Sensory and motor denervation influences epidermal thickness inrat foot glabrous skin, Exp Neurol 1997; 147:452-462 (see page 459).Finally, it is known to administer a botulinum toxin to the foot totreat excessive foot sweating (Katsambas A., et al., Cutaneous diseasesof the foot: Unapproved treatments, Clin Dermatol 2002November-December; 20(6):689-699; Sevim, S., et al., Botulinum toxin—Atherapy for palmar and plantar hyperhidrosis, Acta Neurol Belg 2002December, 102(4):167-70), spastic toes (Suputtitada, A., Local botulinumtoxin type A injections in the treatment of spastic toes, Am J Phys MedRehabil 2002 October; 81(10):770-5), idiopathic toe walking (Tacks, L.,et al., Idiopathic toe walking: Treatment with botulinum toxin Ainjection, Dev Med Child Neurol 2002; 44(Suppl 91):6), and foot dystonia(Rogers J., et al., Injections of botulinum toxin A in foot dystonia,Neurology 1993 April; 43(4 Suppl 2)).

Tetanus toxin, as wells as derivatives (i.e. with a non-native targetingmoiety), fragments, hybrids and chimeras thereof can also havetherapeutic utility. The tetanus toxin bears many similarities to thebotulinum toxins. Thus, both the tetanus toxin and the botulinum toxinsare polypeptides made by closely related species of Clostridium(Clostridium tetani and Clostridium botulinum, respectively).Additionally, both the tetanus toxin and the botulinum toxins aredichain proteins composed of a light chain (molecular weight about 50kD) covalently bound by a single disulfide bond to a heavy chain(molecular weight about 100 kD). Hence, the molecular weight of tetanustoxin and of each of the seven botulinum toxins (non-complexed) is about150 kD. Furthermore, for both the tetanus toxin and the botulinumtoxins, the light chain bears the domain which exhibits intracellularbiological (protease) activity, while the heavy chain comprises thereceptor binding (immunogenic) and cell membrane translocationaldomains.

Further, both the tetanus toxin and the botulinum toxins exhibit a high,specific affinity for ganglioside receptors on the surface ofpresynaptic cholinergic neurons. Receptor mediated endocytosis oftetanus toxin by peripheral cholinergic neurons results in retrogradeaxonal transport, blocking of the release of inhibitoryneurotransmitters from central synapses and a spastic paralysis.Contrarily, receptor mediated endocytosis of botulinum toxin byperipheral cholinergic neurons results in little if any retrogradetransport, inhibition of acetylcholine exocytosis from the intoxicatedperipheral motor neurons and a flaccid paralysis.

Finally, the tetanus toxin and the botulinum toxins resemble each otherin both biosynthesis and molecular architecture. Thus, there is anoverall 34% identity between the protein sequences of tetanus toxin andbotulinum toxin type A, and a sequence identity as high as 62% for somefunctional domains. Binz T. et al., The Complete Sequence of BotulinumNeurotoxin Type A and Comparison with Other Clostridial Neurotoxins, JBiological Chemistry 265(16); 9153-9158:1990.

Acetylcholine

Typically only a single type of small molecule neurotransmitter isreleased by each type of neuron in the mammalian nervous system,although there is evidence which suggests that several neuromodulatorscan be released by the same neuron. The neurotransmitter acetylcholineis secreted by neurons in many areas of the brain, but specifically bythe large pyramidal cells of the motor cortex, by several differentneurons in the basal ganglia, by the motor neurons that innervate theskeletal muscles, by the preganglionic neurons of the autonomic nervoussystem (both sympathetic and parasympathetic), by the bag 1 fibers ofthe muscle spindle fiber, by the postganglionic neurons of theparasympathetic nervous system, and by some of the postganglionicneurons of the sympathetic nervous system. Essentially, only thepostganglionic sympathetic nerve fibers to the sweat glands, thepiloerector muscles and a few blood vessels are cholinergic as most ofthe postganglionic neurons of the sympathetic nervous system secret theneurotransmitter norepinephrine. In most instances acetylcholine has anexcitatory effect. However, acetylcholine is known to have inhibitoryeffects at some of the peripheral parasympathetic nerve endings, such asinhibition of heart rate by the vagal nerve.

The efferent signals of the autonomic nervous system are transmitted tothe body through either the sympathetic nervous system or theparasympathetic nervous system. The preganglionic neurons of thesympathetic nervous system extend from preganglionic sympathetic neuroncell bodies located in the intermediolateral horn of the spinal cord.The preganglionic sympathetic nerve fibers, extending from the cellbody, synapse with postganglionic neurons located in either aparavertebral sympathetic ganglion or in a prevertebral ganglion. Since,the preganglionic neurons of both the sympathetic and parasympatheticnervous system are cholinergic, application of acetylcholine to theganglia will excite both sympathetic and parasympathetic postganglionicneurons.

Acetylcholine activates two types of receptors, muscarinic and nicotinicreceptors. The muscarinic receptors are found in all effector cellsstimulated by the postganglionic, neurons of the parasympathetic nervoussystem as well as in those stimulated by the postganglionic cholinergicneurons of the sympathetic nervous system. The nicotinic receptors arefound in the adrenal medulla, as well as within the autonomic ganglia,that is on the cell surface of the postganglionic neuron at the synapsebetween the preganglionic and postganglionic neurons of both thesympathetic and parasympathetic systems. Nicotinic receptors are alsofound in many nonautonomic nerve endings, for example in the membranesof skeletal muscle fibers at the neuromuscular junction.

Acetylcholine is released from cholinergic neurons when small, clear,intracellular vesicles fuse with the presynaptic neuronal cell membrane.A wide variety of non-neuronal secretory cells, such as, adrenal medulla(as well as the PC12 cell line) and pancreatic islet cells releasecatecholamines and parathyroid hormone, respectively, from largedense-core vesicles. The PC12 cell line is a clone of ratpheochromocytoma cells extensively used as a tissue culture model forstudies of sympathoadrenal development. Botulinum toxin inhibits therelease of both types of compounds from both types of cells in vitro,permeabilized (as by electroporation) or by direct injection of thetoxin into the denervated cell. Botulinum toxin is also known to blockrelease of the neurotransmitter glutamate from cortical synaptosomescell cultures.

A neuromuscular junction is formed in skeletal muscle by the proximityof axons to muscle cells. A signal transmitted through the nervoussystem results in an action potential at the terminal axon, withactivation of ion channels and resulting release of the neurotransmitteracetylcholine from intraneuronal synaptic vesicles, for example at themotor endplate of the neuromuscular junction. The acetylcholine crossesthe extracellular space to bind with acetylcholine receptor proteins onthe surface of the muscle end plate. Once sufficient binding hasoccurred, an action potential of the muscle cell causes specificmembrane ion channel changes, resulting in muscle cell contraction. Theacetylcholine is then released from the muscle cells and metabolized bycholinesterases in the extracellular space. The metabolites are recycledback into the terminal axon for reprocessing into further acetylcholine.

What is needed therefore is a method for effectively treatingneuropsychiatric and/or neurological disorders, such as a thalamicallymediated disorders, by peripheral administration of a pharmaceutical.

SUMMARY

The present invention meets this need and provides medicaments andmethods for effectively treating neuropsychiatric and/or neurologicaldisorders, such as thalamically mediated disorders by peripherallyadministering a botulinum toxin.

The following definitions apply herein.

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means ±10% of the numerical value orrange recited or claimed.

“Intramuscular” or “intramuscularly” means into or within (as inadministration or injection of a botulinum toxin into) a striated orvoluntary muscle, and excludes into or within a smooth or involuntarymuscle.

“Locally administering” means directly administering a pharmaceutical ator to the vicinity of a site on or within an animal body, at which sitea biological effect of the pharmaceutical is desired. Locallyadministering excludes systemic routes of administration, such asintravenous or oral administration.

A “neurological (or neurologic) disorder” is a central nervous systemmalfunction such as epilepsy, chronic pain due to central sensitization,central post stroke pain, regional pain syndrome and phantom limb pain.A neurological disorder includes a brain cortical disfunction which ismediated by or influenced by input to the cortex from the thalamus.

“Neuropsychiatric disorder” means a neurological disturbance that istypically labeled according to which of the four mental faculties areaffected, and includes as well any centrally mediated disorder such asCNS generated pain (i.e. allodynia) and a movement disorder, such asepilepsy.

“Peripherally administering” or “peripheral administration” meanssubdermal, intradermal, transdermal, or subcutaneous administration, butexcludes intramuscular administration. “Peripheral” means in a subdermallocation, and excludes visceral sites.

“Trigeminal sensory nerve” means a peripheral, afferent nerve cell ofthe trigeminal nerve which receives or which transmits sensory signalsor information from the periphery to a location within a human brainsuch as the brain stem, thalamus or cortex. Trigeminal sensory nervetherefore excludes trigeminal motor (efferent) nerves. Thus, trigeminalsensory nerves include the trigeminal nerve ophthalmic division,maxillary division, mandibular division, frontal branch, supra orbitalnerve, supra trochlear nerve, infraorbital nerve, lacrimal nerve,nasociliary nerve, superior alveolar nerve, buccal nerve, lingual nerve,inferior alveolar nerve, mental nerve, and auriculotemporal nerve.

In accordance with the present invention, a medicament and a method isprovided for preventing or for treating a chronic neurological disorder,such as a thalamically mediated disorder. In some embodiments, themedicament can comprise a botulinum toxin for contacting to one or moretrigeminal sensory nerves of a patient, thereby preventing or treating achronic neurological disorder, such as the thalamically mediateddisorder. In some embodiments, the botulinum toxin is administeredperipherally to a trigeminal sensory nerve or to a vicinity of atrigeminal nerve such that the botulinum toxin contacts the trigeminalnerve. Non-limiting examples of trigeminal sensory nerves include anophthalmic nerve, maxillary nerve, mandibular nerve, frontal branch,supra orbital nerve, supra trochlear nerve, lacrimal nerve, nasociliarynerve, infraorbital nerve, superior alveolar nerve, buccal nerve,lingual nerve, inferior alveolar nerve, mental nerve or auriculotemporalnerve.

Further in accordance with the present invention, the method comprisescontacting a trigeminal nerve and further contacting a spinal nerve thatsends afferent fibres to a thalamus. In some embodiments, the botulinumtoxin is administered peripherally to a sensory nerve or to a vicinityof a sensory nerve such that the botulinum toxin contacts the sensorynerve. Non-limiting examples of a spinal nerve include a lesseroccipital nerve or a greater occipital nerve.

Still further in accordance with the present invention, a medicamentwithin the scope of the present invention can be effective to prevent ortreat thalamically mediated or influenced disorders such as epilepsy,chronic pain, or both. Non-limiting examples of chronic pain is centralsensitization chronic pain, central post stroke pain, regional pain,phantom limb pain, or demyelinating disease pain.

In some embodiments, the botulinum toxin is administered subcutaneously,intradermally or subdermally. In some embodiments, about 1 unit to about3000 units of a botulinum toxin are administered to each nerve. In someembodiments, about 1 unit to about 100 units of a botulinum toxin isadministered to each nerve.

Methods and medicaments for treating neuropsychiatric disordersaccording to my invention can comprise a botulinum toxin forperipherally administering to a patient. The botulinum neurotoxin isadministered in a therapeutically effective amount to alleviate at leastone symptom of a neuropsychiatric disorder. The botulinum neurotoxin mayalleviate symptoms associated with the neuropsychiatric disorder byreducing secretions of neurotransmitter from neurons exposed to thebotulinum neurotoxin.

A suitable botulinum neurotoxin for use in a method according to myinvention can be a neurotoxin made by a bacterium, for example, theneurotoxin may be made from a Clostridium botulinum, Clostridiumbutyricum, or Clostridium baratii. The botulinum toxin may be abotulinum toxin type A, type B, type C₁, type D, type E, type F, or typeG. The botulinum toxin can be administered in an amount of between about10⁻³ U/kg and about 20 U/kg. “U/kg” is an abbreviation for units perkilogram of patient weight. The effects of the botulinum toxin canpersist for between about 1 month and 5 years, and can be permanent,that provide a cure for a neuropsychiatric disorder.

Botulinum neurotoxins suitable for use in the include invention includenaturally produced as well recombinantly made botulinum neurotoxins,such as botulinum toxins produced by E. coli. In addition oralternatively, the neurotoxin can be a modified neurotoxin, that is aneurotoxin which has at least one of its amino acids deleted, modifiedor replaced, as compared to a native or the modified neurotoxin can be arecombinant produced neurotoxin or a derivative or fragment thereof. Theneurotoxins are still able to inhibit a neurotransmitter release.

The botulinum neurotoxin is administered through a peripheral route andthereby to a site within the brain that is believed to be involved inthe neuropsychiatric disorder being treated. Alternately, the botulinumneurotoxin can act to reduce peripheral sensory input to a brainlocation. The botulinum neurotoxin can be peripherally administered soas to reduce afferent (sensory) input to, for example, a lower brainregion, the pontine region, the pedunculopontine nucleus, the locuscoeruleus, or to the ventral tegmental area, for example. The botulinumneurotoxin can alleviate the symptom that is associated with ordependant upon a neurotransmitter release. The botulinum neurotoxin mayalso restore a balance between two neuronal systems to alleviate aneuropsychiatric disorder. The botulinum neurotoxin administered to thepatient can inhibit acetylcholine release from cholinergic neurons, andcan potentially inhibit dopamine release from dopaminergic neurons, andrelease of norepinephrine from noradrenergic neurons.

The neuropsychiatric disorders treated in accordance with the methodsdisclosed herein include, and are not limited to, schizophrenia,Alzheimer's disease, mania, and anxiety. The botulinum neurotoxin canalleviate a positive symptom associated with the neuropsychiatricdisorder, for example schizophrenia, and can begin alleviate thesymptoms within a few hours to up to several (two) weeks afteradministration.

I have found that a botulinum toxin, such as botulinum toxin type A, canbe peripherally administered in amounts between about 10⁻⁴ U/kg andabout 20 U/kg to alleviate a neuropsychiatric disorder experienced by ahuman patient. Preferably, the botulinum toxin used is peripherallyadministered in an amount of between about 10⁻³ U/kg and about 1 U/kg.Most preferably, the botulinum toxin is administered in an amount ofbetween about 0.1 unit and about 10 units. Significantly, theneuropsychiatric disorder alleviating effect of the present disclosedmethods can persist for between about 2 months to about 6 months whenadministration is of aqueous solution of the neurotoxin, and for up toabout five years when the neurotoxin is administered as a controlledrelease implant.

A particular amount of a botulinum neurotoxin administered according toa method within the scope of the disclosed invention can vary accordingto the particular characteristics of the neuropsychiatric disorder beingtreated, including its severity and other various patient variablesincluding size, weight, age, and responsiveness to therapy. To guide thepractitioner, typically, no less than about 1 unit and no more thanabout 50 units of a botulinum toxin type A (such as BOTOX®) isadministered per injection site, per patient treatment session. For abotulinum toxin type A such as DYSPORT®, no less than about 2 units andno more about 200 units of the botulinum toxin type A are administeredper administration or injection site, per patient treatment session. Fora botulinum toxin type B such as MYOBLOC®, no less than about 40 unitsand no more about 2500 units of the botulinum toxin type B areadministered per administer or injection site, per patient treatmentsession. Less than about 1, 2 or 40 units (of BOTOX®, DYSPORT® andMYOBLOC® respectively) can fail to achieve a desired therapeutic effect,while more than about 50, 200 or 2500 units (of BOTOX®, DYSPORT® andMYOBLOC® respectively) can result in clinically observable and undesiredmuscle hypotonicity, weakness and/or paralysis.

More preferably: for BOTOX® no less than about 2 units and no more about20 units of a botulinum toxin type A; for DYSPORT® no less than about 4units and no more than about 100 units, and; for MYOBLOC®, no less thanabout 80 units and no more than about 1000 units are, respectively,administered per injection site, per patient treatment session.

Most preferably: for BOTOX® no less than about 5 units and no more about15 units of a botulinum toxin type A; for DYSPORT® no less than about 20units and no more than about 75 units, and; for MYOBLOC®, no less thanabout 200 units and no more than about 750 units are, respectively,administered per injection site, per patient treatment session. It isimportant to note that there can be multiple injection sites (i.e. apattern of injections) for each patient treatment session.

My invention can also be used to prevent development of aneuropsychiatric disorder by administering a botulinum toxin to or tothe vicinity of a trigeminal sensory nerve of the patient with apropensity to develop a neuropsychiatric disorder, thereby preventingdevelopment of the neuropsychiatric disorder. A patient with apropensity to develop a neuropsychiatric disorder is one who shows agenetic (i.e. family history) risk factor or behaviors which though nottruly aberrant point to progression towards a neuropsychiatric disorder.

DRAWINGS

The following drawings are presented to assist understanding of aspectsand features of the present invention.

FIG. 1 is a cross sectional dorsal view of the brain stem without thecerebellum, showing locations of trigeminal nuclei.

FIG. 2 is a representation of the locations of trigeminal nerves andspinal nerves in a human head.

DESCRIPTION

The present invention is based, in part, upon the discovery thatperipheral administration of a botulinum toxin can treat (includingalleviate and/or prevent) a variety of neurological disorders, such as athalamically mediated neurological disorders. Non-limiting examples ofthalamically mediated disorders include epilepsy, chronic pain (such ascentral sensitization chronic pain, central post stroke pain, regionalpain, phantom limb pain, or demyelinating disease pain), reflexsympathetic dystrophy, allodynic states; chronic neurological conditionsin which kindling is part of the disease process, mood disorders(including bipolar disease) and movement disorders.

In some embodiments of my invention, a botulinum toxin can beadministered to prevent development of a neurological disorder (such asa thalamically mediated disorder) in a patient with a propensity to sucha disorder. A patient with a propensity to develop a thalamicallymediated disorder is one who shows a genetic (e.g., family history) riskfactor or behaviors which, though not truly aberrant, point toprogression towards a thalamically mediated disorder. In someembodiments, a botulinum toxin is administered to a patient with suchpropensity prior to the development of a thalamically mediated disorder.

In some embodiments, a botulinum toxin may be administered to treat apatient with a thalamically mediated disorder. A patient is treated whenthe administered botulinum toxin is effective to relieve the patientfrom the symptoms of the thalamically mediated disorder for a durationof time. In some embodiments, a patient treated in accordance with thepresent invention experiences a reduction in the symptoms of thethalamically mediated disorder for more than a day. In some embodiments,a patient treated in accordance with the present invention experiences areduction in the symptoms of the thalamically mediated disorder for morethan a month. In some embodiments, a patient treated in accordance withthe present invention experiences a reduction in the symptoms of thethalamically mediated disorder for more than six months.

Without wishing to be bound by theory a physiological mechanism can beset forth to explain the efficacy of the present invention. Thus, it isknown that a neurological disorder can be due to a cortical disfunctionor dysregulation. A cortical dysregulation, such as an episodicparoxysmal cortical dysregulation, can be influenced by stimulation ofthe cortex through projections received by the cortex from the thalamus.The thalamus in turn can receive afferent fibres carrying signals(input) from peripheral sensory nerves. Thus, it can be postulated thatsensory input from the periphery, to thalamus to cortex can cause or cancontribute to genesis of a cortical disfunction. Hence, reduction of aperipheral sensory input to the thalamus can treat a corticaldisfunction.

A kindling theory can explain episodes of cortical dysfunction (and anensuing neurological disorder) occurring over time without or withreduced the peripheral sensory stimulus to the thalamus. Thus, aneurological disorder can be manifested as a cortical disfunctionmediated or influenced by thalamic input. A thalamically mediateddisorder of the cortex can result in episodic paroxysmal corticaldysregulation, as the cortex is repeatedly stimulated (indirectly) byperipheral sensory nerves that terminate in the thalamus. Over timeepisodes of cortical dysfunction, and the resulting thalamicallymediated disorder, can occur without or with reduced the peripheralsensory stimulus. Such an occurrence of cortical dysfunction without orwith a reduced sensory input can be referred to as a kindling effect.For example, it can be postulated that an episode of epilepsy or paincan be induced by repeated peripheral sensory inputs. Thus, over time,the cortex can become kindled, or sensitized, such that future episodesof epilepsy or pain can occur even without or with much less peripheralsensory input to. See Post R M et al., Shared mechanisms in affectiveillness, epilepsy, and migraine, Neurology. 1994; 44 (suppl 7:S37-S47);Goddard G V et al., A permanent change in brain function resulting fromdaily electrical stimulation, Exp Neurol. 1969; 25:295-330; Post R M,Transduction of psychosocial stress into the neurobiology of recurrentaffective disorder, AM J Psychiatry, 1992; 149:999-1010; and Endicott NA, Psychophysiological correlates of “bipolarity”, J Affect Disord.1989; 17:47-56.

Thus, peripheral administration of a botulinum toxin in accordance withthe present invention can be carried out to decrease sensory stimulationfrom the periphery of the central nervous system, and thereby preventsfurther kindling or reduce the kindling effect upon generation of aneurological disorder, such as thalamically mediated disorder. Thisdesired therapeutic effect of peripheral administration of a botulinumtoxin is independent of muscle relaxation. In some embodiments of myinvention, the administration of botulinum toxin is not into muscles.Further, the suppressive effect provided by the utilized botulinum toxincan persist for a relatively long period of time, for example, for morethan two months, and potentially for several years.

In some embodiments, the botulinum toxin can be administered to and/oraround the vicinity of a trigeminal nerve, such that the botulinum toxincontacts the trigeminal nerve, such as a trigeminal sensory nerve. Insome embodiments, the botulinum toxin may be administered to and/oraround the vicinity of a trigeminal ganglion, such that the botulinumtoxin contacts the trigeminal ganglion. In some embodiments, thebotulinum toxin can be administered to and/or around the vicinity of aspinal nerve such that the botulinum toxin contacts the spinal nerve,wherein the spinal nerve sends an afferent to or terminates in thethalamus. The term spinal nerve generally refers to the mixed spinalnerve, which is formed from the dorsal and ventral roots that come outof the spinal cord. The spinal nerve is the portion that passes out ofthe vertebrae through the intervertebral foramen. In some embodiments,the botulinum toxin may be administered to and/or around the vicinity ofthe trigeminal nerve, to and/or around the trigeminal ganglion, and toand/or around the vicinity of a spinal nerve, wherein the spinal nervesends an afferent to or terminates in the thalamus.

In some embodiments, a botulinum toxin is administered to and/or aroundthe vicinity of a trigeminal nerve, such that the botulinum toxincontacts the trigeminal nerve. As set forth above, the desiredtherapeutic effect of peripheral administration of a botulinum toxin canbe due to a down regulation of sensory trigeminal input to the cortex.Alternately, the botulinum toxin may exert a direct central effect uponretrograde transports up the trigeminal nerve to the thalamus. Forexample, it has been demonstrated that peripheral, subcutaneousadministration of a botulinum toxin can cause a reduction in thesensitization level of central (dorsal horn) neurons which areanatomically distant from the peripheral botulinum toxin injection site.Aoki K., et al., Mechanisms of the antinociceptive effect ofsubcutaneous Botox: Inhibition of peripheral and central nociceptiveprocessing, Cephalalgia 2003 September; 23(7):649 ABS P3I14; Cui M., etal., Mechanisms of the antinociceptive effect of subcutaneous Botox:Inhibition of peripheral and central nociceptive processing, NaunynSchmiedebergs Arch Pharmacol 2002; 365 (Supp) 2):R17.

Thus, once present in the thalamus, the botulinum toxin can act candecrease the ability of the thalamic neurons to stimulate the cortex,and thereby treat a thalamically mediated disorder. Hence,administration of a botulinum toxin according to the present inventioncan be effective to reduce trigeminal sensory stimulation in thethalamus, raising a threshold level for neuronal firing at the corticallevel, and thereby removing kindling input to the cortex to permittreatment of a neurological disorder, such as a thalamically mediateddisorder. See Bolay, H., et al., Intrinsic brain activity triggerstrigeminal meningeal afferents in a migraine model, Nature Medicine,vol. 8 (2); February 2002: 136-142 (botulinum toxin can be used tochange/ameliorate the progression of chronic migraines, and there isevidence for the involvement of the trigeminal nerve in the genesis ofmigraine headaches); Durham P. et al., Regulation of calcitoningene-related peptide secretion from trigeminal nerve cells by botulinumtoxin type A: implications for migraine therapy, Headache 2004 January;44(1):35-43 (botulinum toxin can be used to treat migraine because ofthe ability of the botulinum toxin to repress calcitonin gene-relatedpeptide release from trigeminal sensory neurons); and Aoki K., et al,Evidence for antinociceptive activity of botulinum toxin type A in painmanagement, Headache 2003 July; 43(Suppl 1):S9-S15 (There is evidencethat a botulinum toxin administered to the region of a sensory nerve,such as a trigeminal nerve, can reduce central sensitization).

A botulinum toxin can be administered to and/or around one or moretrigeminal nerves. These trigeminal nerves include, and are not limitedto, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supra trochlear nerve, infraorbital nerve, lacrimalnerve, nasociliary nerve, superior alveolar nerve, buccal nerve, lingualnerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve andfrontal branches of the trigeminal nerve. See FIG. 2. In someembodiments, botulinum toxin is administered to only one trigeminalnerve. In some embodiments, botulinum toxin is administered to more thanone trigeminal nerve. In some embodiments, botulinum toxin may beadministered to the trigeminal nerves simultaneously. In someembodiments, botulinum toxin may be administered to the trigeminalnerves sequentially.

In some embodiments, a botulinum toxin is administered to or around thevicinity of a spinal nerve, wherein the spinal nerve sends an afferentto or terminates in the thalamus. These spinal nerves include, and arenot limited to, the lesser occipital nerve and the greater occipitalnerve. See FIG. 2. In some embodiments, botulinum toxin is administeredto only one spinal nerve. In some embodiments, botulinum toxin isadministered to more than one spinal nerve. In some embodiments,botulinum toxin may be administered to the spinal nerves simultaneously.In some embodiments, botulinum toxin may be administered to the spinalnerves sequentially.

In some embodiments, a botulinum toxin is administered to or around thevicinity of one or more trigeminal nerve, and one or more spinal nerve,wherein the spinal nerve sends an afferent to or terminates in thethalamus. In some embodiments, botulinum toxin is administered to theophthalmic nerve, maxillary nerve, mandibular nerve, supra orbitalnerve, supra trochlear nerve, infraorbital nerve, lacrimal nerve,nasociliary nerve, superior alveolar nerve, buccal nerve, lingual nerve,inferior alveolar nerve, mental nerve, auriculotemporal nerve, frontalbranch, lesser occipital nerve, and greater occipital nerve. In someembodiments, botulinum toxin is administered to these nervessimultaneously. In some embodiments, botulinum toxin may be administeredto these nerves sequentially.

The botulinum toxin can be administered to any region of the nervesindicated herein. In some embodiments, the botulinum toxin isadministered to the nerve endings. For example, the botulinum toxin maybe administered subcutaneously, intradermally and/or subdermally.

The botulinum toxins used in accordance with the invention can inhibittransmission of chemical or electrical signals between select neuronalgroups that are involved in generation, progression and/or maintenanceof a thalamically mediated disorder. The botulinum toxins used caninhibit neurotransmission by reducing or preventing exocytosis of aneurotransmitter from particular neurons exposed to the neurotoxin. Insome embodiments, the botulinum toxins can reduce neurotransmission byinhibiting the generation of action potentials of particular neuronsexposed to the toxin.

Examples of suitable botulinum toxins which may be used to prevent ortreat thalamically mediated disorders include botulinum toxins made fromClostridium bacteria, such as Clostridium botulinum, Clostridiumbutyricum and Clostridium barati. The botulinum toxins may be selectedfrom a group of botulinum toxin types A, B, C (e.g., C₁), D, E, F, andG. In some embodiments, the botulinum toxin administered to the patientis botulinum toxin type A. Botulinum toxin type A is desirable due toits high potency in humans, ready availability, and known use for thetreatment of muscle disorders when administered by intramuscularinjection.

In some embodiments, the present invention also includes the use of (a)botulinum toxins obtained or processed by bacterial culturing, toxinextraction, concentration, preservation, freeze drying, and/orreconstitution; and/or (b) modified or recombinant botulinum toxins,that is botulinum toxins that have had one or more amino acids or aminoacid sequences deliberately deleted, modified or replaced by knownchemical/biochemical amino acid modification procedures or by use ofknown host cell/recombinant vector recombinant technologies, as well asderivatives or fragments of neurotoxins so made. These botulinum toxinvariants should retain the ability to inhibit neurotransmission betweenor among neurons, and some of these variants may provide increaseddurations of inhibitory effects as compared to native botulinum toxins,or may provide enhanced binding specificity to the neurons exposed tothe botulinum toxins. These botulinum toxin variants may be selected byscreening the variants using conventional assays to identify neurotoxinsthat have the desired physiological effects of inhibitingneurotransmission.

Botulinum toxins suitable for use in the include invention includenaturally produced as well recombinantly made botulinum toxins, such asbotulinum toxins produced by E. coli. In some embodiments, the toxin maybe a modified toxin, that is, a neurotoxin which has at least one of itsamino acids deleted, modified or replaced, as compared to a nativetoxin. In some embodiments, the toxin is a chimera toxin.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

In some embodiments, a composition may only comprise a single type of abotulinum toxin, such as a botulinum toxin type A, as the activeingredient to suppress neurotransmission. In some embodiments, acomposition may include two or more types of botulinum toxins, which mayprovide enhanced therapeutic effects upon a thalamically mediateddisorder. For example, a composition administered to a patient mayinclude botulinum toxin type A and botulinum toxin type B. Administeringa single composition containing two different botulinum toxins maypermit the effective concentration of each of the botulinum toxins to belower than if a single botulinum toxin is administered to the patientwhile still achieving the desired therapeutic effects. The compositionadministered to the patient may also contain other pharmaceuticallyactive ingredients, such as, protein receptor or ion channel modulators,in combination with the botulinum toxin or botulinum toxins. Thesemodulators may contribute to the reduction in neurotransmission betweenthe various neurons. For example, a composition may contain gammaaminobutyric acid (GABA) type A receptor modulators that enhance theinhibitory effects mediated by the GABA_(A) receptor. The GABA_(A)receptor inhibits neuronal activity by effectively shunting current flowacross the cell membrane. GABA_(A) receptor modulators may enhance theinhibitory effects of the GABA_(A) receptor and reduce electrical orchemical signal transmission from the neurons. Examples of GABA_(A)receptor modulators include benzodiazepines, such as diazepam, oxazepam,lorazepam, prazepam, alprazolam, halazepam, chlordiazepoxide, andclorazepate. Compositions may also contain glutamate receptor modulatorsthat decrease the excitatory effects mediated by glutamate receptors.Examples of glutamate receptor modulators include agents that inhibitcurrent flux through AMPA, NMDA, and/or kainate types of glutamatereceptors. The compositions may also include agents that modulatedopamine receptors, such as antipsychotics, norepinephrine receptors,and/or serotonin receptors. The compositions may also include agentsthat affect ion flux through voltage gated calcium channels, potassiumchannels, and/or sodium channels. Thus, the compositions used to treatthalamically mediated disorders may include one or more botulinumtoxins, in addition to ion channel receptor modulators that can reduceneurotransmission.

In some embodiments, a composition comprising a botulinum toxin isadministered peripherally, and a composition containing otherpharmaceutical agents, such as antipsychotics, that can cross the bloodbrain barrier can be administered systemically, such as by intravenousadministration, to achieve the desired therapeutic effects.

In some embodiments, the botulinum toxin may be administered to thepatient in conjunction with a solution or composition that locallydecreases the pH of the target tissue environment. For example, asolution containing hydrochloric acid may be used to locally andtemporarily reduce the pH of the target tissue environment to facilitatetranslocation of the neurotoxin across cell membranes. The reduction inlocal pH may be desirable when the composition contains fragments ofbotulinum toxins that may not have a functional targeting moiety (e.g.,a portion of the toxin that binds to a neurotoxin receptor), and/or atranslocation domain). By way of example, and not by way of limitation,a fragment of a botulinum toxin that comprises the proteolytic domain ofthe toxin may be administered to the patient in conjunction with anagent that decreases the local pH of the target tissue. Without wishingto be bound by any particular theory, it is believed that the lower pHmay facilitate the translocation of the proteolytic domain across thecell membrane so that the neurotoxin fragment can exert its toxiceffects within the cell. The pH of the target tissue is only temporarilylowered so that neuronal and/or glial injury is reduced.

Methods of administration include injecting a composition (e.g. asolution) comprising the botulinum toxin as described above. In someembodiments, the method of administration includes implanting acontrolled release system that controllably releases the botulinum toxinto the target trigeminal tissue. For example, the botulinum toxin can beadministered peripherally using a subdermal implant. Such controlledrelease systems reduce the need for repeat injections. Diffusion ofbiological activity of a botulinum toxin within a tissue appears to be afunction of dose and can be graduated. Jankovic J., et al Therapy WithBotulinum Toxin, Marcel Dekker, Inc., (1994), page 150. Thus, diffusionof botulinum toxin can be controlled to reduce potentially undesirableside effects that may affect the patient's cognitive abilities. Forexample, the botulinum toxin may be administered so that the botulinumtoxin primarily effects neural systems believed to be involved in aselected thalamically mediated disorder, and does not have negativelyadverse effects on other neural systems.

The present invention is also based upon the discovery that peripheraladministration of a botulinum neurotoxin can provide significant andlong lasting relief from a variety of different neuropsychiatricdisorders.

Without wishing to be bound by theory, peripheral administration of abotulinum toxin according to the methods disclosed herein is believed topermit a botulinum neurotoxin to either be administered (by retrogradeprogression of the botulinum toxin) to a site within a patient's craniumand/or to reduce afferent, sensory input to a site within the patients'cranium to thereby influence intracranial neurons involved in aneuropsychiatric disorder.

Thus, neuropsychiatric disorders are believed to originate from episodicparoxysmal cortical dysregulation, influenced by various stressfactors¹. Over time these episodes of cortical dysfunction, and theresulting neuropsychiatric disorder, can occur without stressor inputs.Hence a kindling model^(2,3) for development of a neuropsychiatricdisorder is appropriate. Under a kindling model repeated low levels ofstimulation can over time result in occurrence of a neuropsychiatricdisorder without further sensory input. It is known that the brain canbecome kindled or sensitized, such that pathways inside the centralnervous system are reinforced and future episodes of, for example,depression, hypomania, mania, bipolar disorder or epilepsy can thenoccur independently of an outside stimulus with greater and greaterfrequency. My kindling theory of neuropsychiatric disorders is supportedby descriptions states of physiologic responsivity and heightenedreactivity⁴. A botulinum toxin can be used to decrease afferentstimulation of the central nervous system and thereby prevent furtherkindling of a neuropsychiatric disorder. ¹ Post R M, Silberstein S D.Shared mechanisms in affective illness, epilepsy, and migraine.Neurology. 1994; 44(suppl 7):S37-S47.² Goddard G V, McIntyre D C, LeechC K, A permanent change in brain function resulting from dailyelectrical stimulation Exp Neurol. 1969; 25:295-330.³ Post R M,Transduction of psychosocial stress into the neurobiology of recurrentaffective disorder. AM J Psychiatry, 1992; 149:999-1010.⁴ Endicott N APsychophysiological correlates of “bipolarity.” J Affect Disord. 1989;17:47-56.

Thus, a neuropsychiatric disorder can be treated by decreasing afferentstimulation of the cortex. In particular, administration of a botulinumtoxin to a site or sites around a trigeminal nerve and c₂/c₃ afferentthe result can be a decreased responsiveness in the nucleus caudalis.This in turn can decrease thalamic and subsequent cortical afferent,sensory input. It is known that c₂/c₃ afferents project to thetrigeminal complex and are involved with sensitization of 2^(nd) and3^(rd) order neurons. Significantly, it has been demonstrated thatperipheral, subcutaneous administration of a botulinum toxin can cause areduction in the sensitization level of central (dorsal horn) neuronswhich are anatomically distant from the peripheral botulinum toxininjection site. Aoki K., et al., Mechanisms of the antinociceptiveeffect of subcutaneous Botox: Inhibition of peripheral and centralnociceptive processing, Cephalalgia 2003 September; 23(7):649 ABS P3114;Cui M., et al., Mechanisms of the antinociceptive effect of subcutaneousBotox: Inhibition of peripheral and central nociceptive processing,Naunyn Schmiedebergs Arch Pharmacol 2002; 365(Suppl 2):R17.

Thus, a botulinum toxin can be used to treat a neuropsychiatric disorderby blocking the progression of a neuropsychiatric disorder that canoccur due to repeated sensory input to the cortex from a peripheraltrigeminal sensory nerve. Notably, it has been reported that a botulinumtoxin can be used to change (ameliorate) the progression of chronicmigraines⁵, and there is evidence for the involvement of the trigeminalnerve in the genesis of migraine headaches. Bolay, H., et al., Intrinsicbrain activity triggers trigeminal meningeal afferents in a migrainemodel, Nature Medicine, vol. 8 (2); February 2002: 136-142.Additionally, there is evidence that a botulinum toxin can be used totreat migraine because of the ability of the botulinum toxin to represscalcitonin gene-related peptide release from trigeminal sensory neurons.Durham P. et al., Regulation of calcitonin gene-related peptidesecretion from trigeminal nerve cells by botulinum toxin type A:implications for migraine therapy, Headache 2004 January; 44(1):35-43.

Thus, peripheral administration of a botulinum toxin, by decreasingafferent trigeminal cortical stimulation, can remove external stressorswhich centrally kindle occurrence of a neuropsychiatric disorder.Conditions that can be treated or attenuated with this approach toreduce cortical sensory input through a trigemino-thalamic routeinclude: central pain syndromes particularly chronic pain syndromes withcentral sensitization; post stroke pain syndrome; reflex sympatheticdystrophy; phantom limb pain; allodynic states; chronic neurologicalconditions in which kindling is part of the disease process; epilepsy;neuropsychiatric disorders, including mood disorders, particularlybipolar disease, and movement disorders.

Thus, a method according to my invention uses a botulinum toxin toproduce a modulating effect on the central nervous system whenadministered (i.e. injected) into a trigeminal nerve branch and/or ansacervicalis branch particularly in the C2 and C3 dermatomes. Thetrigeminal sensory nerve endings that are targeted include thesupra-orbital, supra-trochlear, temporo-auricular, greater and lesseroccipital nerves. This method leads to decreased sensory afferents tothe spinal tract of the nucleus caudalis and thereby decreased centralafferent input to the thalamus and thence to the cortex.

Hence, administration of a botulinum toxin according to my invention iscarried out so to achieve a desired central effect, that is the raisingof a threshold level for neuronal firing at the cortical level, byreducing trigeminal sensory input and thereby removing kindling input tothe cortex. By doing so, a centrally mediated neuropsychiatric disordercan be treated. Thus, the efficacy of the present invention can be dueto a reduction of a kindling effect upon the cortex, as a kindlingeffect reduction results in a slowing down of the progression, or thetreating, of a centrally mediated neuropsychiatric disorder.

There is evidence that a botulinum toxin administered to the region of asensory nerve, such as a trigeminal nerve, can reduce centralsensitization. Aoki K., et al, Evidence for antinociceptive activity ofbotulinum toxin type A in pain management, Headache 2003 July; 43(Suppl1):S9-S15; Durham P., et al., Regulation of calcitonin gene-relatedpeptide secretion from trigeminal nerve cells by botulinum toxin type A:implications for migraine therapy, Headache 2004 January; 44(1):35-43.

Thus, decreasing afferent impulses in the trigeminal innervated regionscan decrease central afferents initially in the brainstem andsubsequently in the thalamus, the sensory cortex, and in the motorcortex. Hence, a neuropsychiatric disorder can be treated by forexample, inhibiting a kindling effect, and down regulating sensory inputto central afferents.

Input to the caudal segment of the spinal trigeminal nucleus from thecervical plexus branches include the greater and lesser occipitalnerves, which travel over the occipital and suboccipital regions. Othernerves include the greater auricular nerve, and the anterior cutaneousnerve of the neck. In a preferred embodiment of my invention a botulinumtoxin is administered delivered to these trigeminal nerve branches whichrun in the dermal region.

The treatment outlined above is expected to down regulate centralnervous system activation and reduce kindling over the long-term. Thiseffect is independent of muscle relaxation. Injections need to be in theregion of the trigeminal and cervical plexus branches, and not inmuscles of the face, neck and head.

The aim of the outlined treatment is to maximize the effects on thecortical homunculus. Using the trigeminal sensory system approach, eachunit of a botulinum toxin delivered has the maximum cortical effects onthe head/face representation in the homunculus, with the least sideeffects. This allows for the maximum central effect of each unit ofbotulinum toxin delivered peripherally.

An alternate theory for the efficacy (therapeutic result) of a methodpracticed according to the present invention rests upon the fact that abotulinum toxin, can inhibit neuronal exocytosis of several differentCNS neurotransmitters, for example acetylcholine. It is known thatcholinergic neurons are present throughout the brain. Additionally,cholinergic nuclei exist in the basal ganglia or in the basal forebrain,with projections to cerebral regions involved in emotion, behavior, andother cognitive functions. Thus, target tissues for a method within thescope of the present invention can include neurotoxin induced reversibledenervation of brain cholinergic systems, such as basal nuclei orpedunculopontine nucleus. For example, peripheral injection orperipheral implantation of a botulinum neurotoxin to or to the vicinityof a trigeminal nerve can permit the botulinum toxin to be retrogradetransported to a cholinergic brain nucleus with the result of (1)downregulation of dopaminergic release from target sites of cholinergicneurons due to the action of the toxin upon cholinergic terminalsprojecting into the ventral tegmental area from pedunculopontinenucleus; and (2) attenuation of ventral tegmental area output due to theaction of the toxin upon cholinergic neurons projecting to the ventraltegmental area.

Alternately, use of a botulinum toxin as set forth herein can inhibit ofexocytosis of nonacetylcholine neurotransmitters. For example, it isbelieved that once the proteolytic domain of a botulinum toxin, isincorporated into a target neuron, the toxin inhibits release of anyneurotransmitter from that neuron. Thus, the botulinum neurotoxin can beperipherally administered to a target brain nuclei containing asubstantial number of dopaminergic neurons so that the neurotoxineffectively inhibits the release of dopamine from those neurons.Similarly, the botulinum neurotoxin can be administered to other nucleisuch as the Raphe nuclei to inhibit serotonin exocytosis, the locuscoeruleus nuclei to inhibit norepinephrine exocytosis.

The botulinum neurotoxins used in accordance with the inventiondisclosed herein can inhibit transmission of chemical or electricalsignals between select neuronal groups that are involved in generation,progression and/or maintenance of a neuropsychiatric disorder. Thebotulinum neurotoxins used, at the dose levels used, are not cytotoxicto the cells that are exposed to the neurotoxin. The botulinumneurotoxins used can inhibit neurotransmission by reducing or preventingexocytosis of a neurotransmitter from particular neurons exposed to theneurotoxin. Alternately, the botulinum neurotoxins can reduceneurotransmission by inhibiting the generation of action potentials ofparticular neurons exposed to the toxin. The neuropsychiatric disordersuppressive effect provided by the utilized botulinum neurotoxin canpersist for a relatively long period of time, for example, for more thantwo months, and potentially for several years.

Examples of suitable botulinum neurotoxins which can be used to treatneuropsychiatric disorders according to my invention disclosed herein,include botulinum neurotoxins made from Clostridium bacteria, such asClostridium botulinum, Clostridium butyricum and Clostridium baratii.The botulinum toxins can selected from a group of botulinum toxin typesA, B, C, D, E, F, and G. In one embodiment of the invention, thebotulinum neurotoxin administered to the patient is botulinum toxin typeA. Botulinum toxin type A is desirable due to its high potency inhumans, ready availability, and known use for the treatment of muscledisorders when administered by intramuscular injection. The presentinvention also includes the use of (a) botulinum neurotoxins obtained orprocessed by bacterial culturing, toxin extraction, concentration,preservation, freeze drying, and/or reconstitution; and/or (b) modifiedor recombinant botulinum neurotoxins, that is botulinum neurotoxins thathave had one or more amino acids or amino acid sequences deliberatelydeleted, modified or replaced by known chemical/biochemical amino acidmodification procedures or by use of known host cell/recombinant vectorrecombinant technologies, as well as derivatives or fragments ofneurotoxins so made. These botulinum neurotoxin variants should retainthe ability to inhibit neurotransmission between or among neurons, andsome of these variants may provide increased durations of inhibitoryeffects as compared to native botulinum neurotoxins, or may provideenhanced binding specificity to the neurons exposed to the botulinumneurotoxins. These botulinum neurotoxin variants may be selected byscreening the variants using conventional assays to identify neurotoxinsthat have the desired physiological effects of inhibitingneurotransmission.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

Although the composition can only contain a single type of a botulinumneurotoxin, such as a botulinum toxin type A, as the active ingredientto suppress neurotransmission, other therapeutic compositions mayinclude two or more types of botulinum neurotoxins, which may provideenhanced therapeutic effects upon a neuropsychiatric disorder. Forexample, a composition administered to a patient may include botulinumtoxin type A and botulinum toxin type B. Administering a singlecomposition containing two different botulinum neurotoxins may permitthe effective concentration of each of the botulinum neurotoxins to belower than if a single botulinum neurotoxin is administered to thepatient while still achieving the desired therapeutic effects. Thecomposition administered to the patient may also contain otherpharmaceutically active ingredients, such as, protein receptor or ionchannel modulators, in combination with the botulinum neurotoxin orbotulinum neurotoxins. These modulators may contribute to the reductionin neurotransmission between the various neurons. For example, acomposition may contain gamma aminobutyric acid (GABA) type A receptormodulators that enhance the inhibitory effects mediated by the GABA_(A)receptor. The GABA_(A) receptor inhibits neuronal activity byeffectively shunting current flow across the cell membrane. GABA_(A)receptor modulators may enhance the inhibitory effects of the GABA_(A)receptor and reduce electrical or chemical signal transmission from theneurons. Examples of GABA_(A) receptor modulators includebenzodiazepines, such as diazepam, oxazepam, lorazepam, prazepam,alprazolam, halazepam, chlordiazepoxide, and clorazepate. Compositionsmay also contain glutamate receptor modulators that decrease theexcitatory effects mediated by glutamate receptors. Examples ofglutamate receptor modulators include agents that inhibit current fluxthrough AMPA, NMDA, and/or kainate types of glutamate receptors. Thecompositions may also include agents that modulate dopamine receptors,such as antipsychotics, norepinephrine receptors, and/or serotoninreceptors. The compositions may also include agents that affect ion fluxthrough voltage gated calcium channels, potassium channels, and/orsodium channels. Thus, the compositions used to treat neuropsychiatricdisorders may include one or more botulinum toxins, in addition to ionchannel receptor modulators that can reduce neurotransmission.

Preferably, the botulinum neurotoxin is peripherally administered byadministering it to or to the vicinity of a trigeminal nerve or to atrigeminal nerve branch or trigeminal ganglion nuclei. This method ofadministration permit the botulinum neurotoxin to be administered toand/or to affect select intracranial target tissues. Methods ofadministration include injection of a solution or composition containingthe botulinum neurotoxin, as described above, and include implantationof a controlled release system that controllably releases the botulinumneurotoxin to the target trigeminal tissue. Such controlled releasesystems reduce the need for repeat injections. Diffusion of biologicalactivity of a botulinum toxin within a tissue appears to be a functionof dose and can be graduated. Jankovic J., et al Therapy With BotulinumToxin, Marcel Dekker, Inc., (1994), page 150. Thus, diffusion ofbotulinum toxin can be controlled to reduce potentially undesirable sideeffects that may affect the patient's cognitive abilities. For example,the botulinum neurotoxin may be administered so that the botulinumneurotoxin primarily effects neural systems believed to be involved in aselected neuropsychiatric disorder, and does not have negatively adverseeffects on other neural systems.

In addition, the botulinum neurotoxin may be administered to the patientin conjunction with a solution or composition that locally decreases thepH of the target tissue environment. For example, a solution containinghydrochloric acid may be used to locally and temporarily reduce the pHof the target tissue environment to facilitate translocation of theneurotoxin across cell membranes. The reduction in local pH may bedesirable when the composition contains fragments of botulinumneurotoxins that may not have a functional targeting moiety (e.g., aportion of the toxin that binds to a neurotoxin receptor), and/or atranslocation domain). By way of example, and not by way of limitation,a fragment of a botulinum toxin that comprises the proteolytic domain ofthe toxin may be administered to the patient in conjunction with anagent that decreases the local pH of the target tissue. Without wishingto be bound by any particular theory, it is believed that the lower pHmay facilitate the translocation of the proteolytic domain across thecell membrane so that the neurotoxin fragment can exert its toxiceffects within the cell. The pH of the target tissue is only temporarilylowered so that neuronal and/or glial injury is reduced.

The botulinum neurotoxin is administered peripherally, and a compositioncontaining other pharmaceutical agents, such as antipsychotics, that cancross the blood brain barrier can be administered systemically, such asby intravenous administration, to achieve the desired therapeuticeffects.

Implants that are employed in accordance with the present invention maycomprise various polymers. For example, a polyanhydride polymer,Gliadel® (Stolle R & D, Inc., Cincinnati, Ohio) a copolymer ofpoly-carboxyphenoxypropane and sebacic acid in a ratio of 20:80 has beenused to make implants, and has been peripherally implanted to treatmalignant gliomas. Polymer and BCNU can be co-dissolved in methylenechloride and spray-dried into microspheres. The microspheres can then bepressed into discs 1.4 cm in diameter and 1.0 mm thick by compressionmolding, packaged in aluminum foil pouches under nitrogen atmosphere andsterilized by 2.2 megaRads of gamma irradiation. The polymer permitsrelease of carmustine over a 2-3 week period, although it can take morethan a year for the polymer to be largely degraded. Brem, H., et al,Placebo-Controlled Trial of Safety and Efficacy of IntraoperativeControlled Delivery by Biodegradable Polymers of Chemotherapy forRecurrent Gliomas, Lancet 345; 1008-1012:1995.

In some embodiments, implants useful in practicing the methods disclosedherein may be prepared by mixing a desired amount of a stabilizedbotulinum toxin (such as non-reconstituted BOTOX® or DYSPORT®) into asolution of a suitable polymer dissolved in methylene chloride. Thesolution may be prepared at room temperature. The solution can then betransferred to a Petri dish and the methylene chloride evaporated in avacuum desiccator. Depending upon the implant size desired and hence theamount of incorporated neurotoxin, a suitable amount of the driedneurotoxin incorporating implant is compressed at about 8000 p.s.i. for5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implantdiscs encapsulating the neurotoxin. See e.g. Fung L. K. et al.,Pharmacokinetics of Interstitial Delivery of Carmustine4-Hydroperoxycyclophosphamide and Paclitaxel From a BiodegradablePolymer Implant in the Monkey Brain, Cancer Research 58; 672-684:1998.

The amount of a botulinum toxin selected for peripheral administrationto a target tissue according to the present disclosed invention can bevaried based upon criteria such as the thalamically mediated disorderbeing treated, its severity, the extent of brain tissue involvement orto be treated, solubility characteristics of the neurotoxin toxin chosenas well as the age, sex, weight and health of the patient. For example,the extent of the area of brain tissue influenced is believed to beproportional to the volume of neurotoxin injected, while the quantity ofthe thalamically mediated disorder suppressant effect is, for most doseranges, believed to be proportional to the concentration of thebotulinum toxin peripherally administered. Methods for determining theappropriate route of administration and dosage are generally determinedon a case by case basis by the attending physician. Such determinationsare routine to one of ordinary skill in the art (see for example,Harrison's Principles of Internal Medicine (1998), edited by AnthonyFauci et al., 14^(th) edition, published by McGraw Hill).

A dose of a non-botulinum toxin type A is an equivalent to a dose ofbotulinum toxin type A if they both have about the same degree ofprevention or treatment when administered to a mammal (although theirduration may differ). The degree of prevention or treatment may bemeasured by the evaluation of the improved patient function criteria setforth below.

The botulinum toxin can be peripherally administered according to thepresent disclosed methods in amounts of between about 10⁻⁴ U/kg to about20 U/kg (units of type A), or an equivalent of U/kg of a non-type Abotulinum toxin. A dose of about 10⁻⁴ U/kg can result in a thalamicallymediated disorder suppressant effect if delivered to a small targetbrain nuclei. Peripheral administration of less than about 10⁻⁴ U/kg ofa botulinum toxin does not result in a significant or lastingtherapeutic result. A peripheral dose of more than about 20 U/kg of abotulinum toxin (such as BOTOX) poses a risk of systemic effects.Accordingly, administration of a botulinum toxin to an intracranialtarget tissue involved in thalamically mediated disorders through aperipheral route as set forth herein can effectively reduce symptomsassociated with the thalamically mediated disorder to be treated withoutcausing significant undesired cognitive dysfunction. Thus, the methodsof the present invention can provide a more selective treatment withfewer undesirable side effects than current systemic therapeuticregimes.

In some embodiments, about 1 unit to about 40 units of botulinum toxintype A, or the equivalent of other types, are administered to atrigeminal and/or spinal nerve in accordance with the present invention.In some embodiments, about 3 units to about 30 units of botulinum toxintype A, or the equivalent of other types, are administered to atrigeminal or spinal nerve in accordance with the present invention. Insome embodiments, about 5 units to about 25 units of botulinum toxintype A, or the equivalent of other types, are administered to atrigeminal or spinal nerve in accordance with the present invention. Insome embodiments, about 5 units to about 15 units of botulinum toxintype A, or the equivalent of other types, are administered to atrigeminal or spinal nerve in accordance with the present invention.

In some embodiments, one or more nerve is injected with a botulinumtoxin to treat a thalamically mediated disorder: supra-orbital nerve(bilaterally about 5 units of type A, or the equivalent of other types,on each side), supra-trochlear nerve (about 5 units of type A, or theequivalent of other types, on each side), frontal branches of thetrigeminal nerve (about 12.5 units type A, or the equivalent of othertypes, each side), auriculotemporal nerve (about 20 units of type A, orthe equivalent of other types, on each side), lesser occipital nerve(about 5 units of type A, or the equivalent of other types, on eachside), and/or greater occipital nerve (about 5 units of type A, or theequivalent of other types, on each side). In some embodiments, the totaldose administered per session is about 105 units of botulinum toxin typeA, or the equivalents of other types.

In some embodiments, the particular amount of a botulinum toxinadministered according to a method within the scope of the disclosedinvention can vary according to the particular characteristics of thethalamically mediated disorder being treated, including its severity andother various patient variables including size, weight, age, andresponsiveness to therapy. As a general guide, typically, no less thanabout 1 unit and no more than about 50 units of a botulinum toxin type A(such as BOTOX®) is administered per injection site, per patienttreatment session. For a botulinum toxin type A such as DYSPORT®, noless than about 2 units and no more about 200 units of the botulinumtoxin type A are administered per administration or injection site, perpatient treatment session. For a botulinum toxin type B such asMYOBLOC®, no less than about 40 units and no more about 2500 units ofthe botulinum toxin type B are administered per administer or injectionsite, per patient treatment session. Less than about 1, 2 or 40 units(of BOTOX®, DYSPORT® and MYOBLOC® respectively) can fail to achieve adesired therapeutic effect, while more than about 50, 200 or 2500 units(of BOTOX®, DYSPORT® and MYOBLOC® respectively) can result in clinicallyobservable and undesired muscle hypotonicity, weakness and/or paralysis.

In some embodiments, for BOTOX®, no less than about 2 units and no moreabout 20 units of a botulinum toxin type A; for DYSPORT® no less thanabout 4 units and no more than about 100 units, and; for MYOBLOC®, noless than about 80 units and no more than about 1000 units are,respectively, administered per injection site, per patient treatmentsession.

In some embodiments, for BOTOX® no less than about 5 units and no moreabout 15 units of a botulinum toxin type A; for DYSPORT® no less thanabout 20 units and no more than about 75 units, and; for MYOBLOC®, noless than about 200 units and no more than about 750 units are,respectively, administered per injection site, per patient treatmentsession. It is important to note that there can be multiple injectionsites (i.e. a pattern of injections) for each patient treatment session.

Significantly, a method within the scope of the present invention canprovide improved patient function. “Improved patient function” can bedefined as an improvement measured by factors such as a reduced pain,reduced time spent in bed, increased ambulation, healthier attitude,more varied lifestyle and/or healing permitted by normal muscle tone.Improved patient function is synonymous with an improved quality of life(QOL). QOL can be assessed using, for example, the known SF-12 or SF-36health survey scoring procedures. SF-36 assesses a patient's physicaland mental health in the eight domains of physical functioning, rolelimitations due to physical problems, social functioning, bodily pain,general mental health, role limitations due to emotional problems,vitality, and general health perceptions. Scores obtained can becompared to published values available for various general and patientpopulations.

A method for treating a thalamically mediated disorder according to theinvention disclosed herein has many benefits and advantages, includingthe following:

1. the symptoms of a neurological disorder, such as a thalamicallymediated disorder, can be dramatically reduced or eliminated.2. the symptoms of a thalamically mediated disorder can be reduced oreliminated for at least about two weeks to about six months perinjection of neurotoxin and for from about one year to about five yearsupon use of a controlled release neurotoxin implant.3. few or no significant undesirable side effects occur from anintradermal or subdermal) injection or implantation of the botulinumtoxin.4. the present methods can result in the desirable side effects ofgreater patient mobility, a more positive attitude, and an improvedquality of life.

The following non-limiting examples provide those of ordinary skill inthe art with possible case scenarios and specific methods to treatconditions within the scope of the present invention and are notintended to limit the scope of the invention. In the following examplesvarious modes of peripheral administration of a botulinum toxin can becarried out. For example, by topical application (cream or transdermalpatch), subcutaneous injection, or subdermal implantation of acontrolled release implant.

EXAMPLES Example 1 Supraorbital and Supratrochlear Administration ofBotulinum Toxin

The supraorbital and supratrochlear nerves innervate the frontal part ofscalp and forehead. Both nerves are branches of the first division orophthalmic branch of the trigeminal nerve. The supraorbital nerve exitsthe skull through the supraorbital foramen that lies in the midpupillaryline, which is approximately 2.5 cm lateral to the facial midline alongthe supraorbital ridge. The supratrochlear nerve exits the skull alongthe upper medial corner of the orbit in the supratrochlear notch, whichis approximately 1.5 cm medial to the supraorbital foramen.

Supraorbital and supratrochlear administration of botulinum toxin may beperformed from either the area of the supraorbital foramen or the areaof the supratrochlear notch. If performed from the supraorbital foramen,the area should be located, and a skin wheal raised at the site. Theneedle is inserted through the anesthetized area and advanced to thebone. Approximately 5 units of botulinum toxin (e.g., type A) isinjected outside the foramen at the level of the inferior frontalismuscle.

The supratrochlear nerve may be reached by advancing the needle 1.5 cmmedial to the junction of the supraorbital ridge and the root of thenose. As before, about 5 units of botulinum toxin (e.g., type A) isinjected.

If the injection is performed from the area of the supratrochlear nerve,a wheal should be placed over the root of the nose at the junction ofthe nasal root and supraorbital ridge. The skin is infiltrated along thelength of the entire eyebrow. When this injection is used, patientsshould be warned about the possibility of swelling in the upper and/orlower eyelids. For this type of injection, about 5 units of botulinumtoxin (e.g., type A) per side is usually sufficient, and no more than 20units should be injected into either side. As with any injection, therisk of ecchymosis or hematoma formation exists.

Example 2 Infraorbital Administration of Botulinum Toxin

The infraorbital nerve innervates the lower eyelid, medial aspect of thecheek, upper lip, and lateral portion of the nose. It is a branch of thesecond division or maxillary branch of the trigeminal nerve. Theinfraorbital nerve exits the skull through the infraorbital foramen,which is 1 cm inferior to the infraorbital ridge and approximately 2.5cm lateral to the facial midline in the midpupillary line. After exitingthe infraorbital foramen, the infraorbital nerve divides into 4branches: the inferior palpebral, internal nasal, external nasal, andsuperior labial branches.

An infraorbital injection may be performed in 2 ways: via directcutaneous injection or via intraoral injection. The infraorbital foramenshould be palpated, and approximately 5 units of botulinum toxin (e.g.,type A) is injected near, but not into, the canal to surround the nerve.

If the injection is to be performed via the intraoral approach, theapplication of a topical anesthetic to the mucosa before injection mayincrease patient comfort. The infraorbital foramen should be palpatedwith the middle finger of one hand while the thumb and index finger ofthe same hand are used to raise the lip. During palpation of theforamen, the needle is inserted into the superior labial sulcus at theapex of the canine fossa. Approximately 5 units of botulinum toxin(e.g., type A) is injected in the vicinity of the infraorbital foramen.

It is advisable to warn patients that swelling of the lower eyelid andecchymosis may occur with the infraorbital injection. In addition, ifanesthetic solution is injected into the orbit, excessive pain,diplopia, exophthalmos, and blindness can occur. The likelihood of thereactions is increased if the needle is placed superior to theinfraorbital rim or into the infraorbital foramen.

Example 3 Mental Nerve Administration of a Botulinum Toxin

The mental nerve innervates the lower lip and chin. It is a branch ofthe third division or mandibular portion of the trigeminal nerve. Themental nerve exits the skull through the mental foramen, which islocated approximately 2.5 cm from the midline of the face in themidpupillary line.

Either a cutaneous or intraoral approach can be used to inject themental nerve. To inject the nerve cutaneously, the foramen should bepalpated, and a wheal of botulinum toxin placed. Then, the needle shouldbe reinserted and advanced to the vicinity of the mental foramen but notinto it. Approximately 5 units of botulinum toxin (e.g., type A) shouldbe injected into the area. Alternatively, when an intraoral approach isused, the foramen should be palpated with the middle finger of one handand the lip lifted by the thumb and index finger of the same hand. Theneedle should be inserted at the inferior labial sulcus at the apex ofthe first bicuspid and 5 units of botulinum toxin (e.g., type A)injected.

Example 4 Use of a Botulinum Toxin to Treat Epilepsy

A 23 year man can presents with chronic seizures dating from childhood.These can involve tonic clonic movements that start in the right arm andprogress up the arm to the face. Eventually he can lose consciousnessand have a generalized body seizure lasting about 3 minutes. Hisneurological examination and head MRI scan can be normal. He can be on 3anticonvulsant medications: Depakote, Tegretol, and Topamax and he canstill have seizures about once a week. The Department of Motor Vehicles(DMV) may not allow him to drive. His treatment history can include 3courses of a botulinum toxin type A using a 4 cc dilution and injectingusing the trigeminal targeting approach as follows: supra-orbital nervebilaterally 5 units each side, supra-trochlear nerve 5 units each side,frontal branches of the trigeminal nerve 12.5 units each side,auriculotemporal nerve 20 units each side, lesser occipital nerve 5units on each side, and greater occipital nerve 5 units on each side.Total dose can be 105 units.

In some embodiments, the referenced botulinum units are units ofbotulinum toxin type A. In some embodiments, the botulinum toxinemployed is not type A, but would have the same unit equivalent as thatof type A. His seizure control can improve 4 weeks after the firsttreatment and he can be currently only on Depakote, and can have beensuccessfully weaned off of the other 2 anticonvulsants. He can beseizure free for 6 months.

Example 5 Use of a Botulinum Toxin to Treat Chronic Pain Syndrome withCentral Sensitization

A 60 year old woman can have a chronic history of fibromyalgia with 18out of 18 positive tender points. Her treatment history can includetricyclic antidepressants and high doses of Neurontin. Despite thesemedications, she can require escalating doses of narcotics to achievepain control. She can develop allodynia of the face, scalp, neck andshoulder girdle, as well as along her extremities. Steroid trigger pointinjections may not provide relief. She can experience chronic dailyheadache. Subsequently, she can be treated with a botulinum toxin typeA, 4 cc dilution, using the trigeminal targeting approach, with 105units at the sites outlined above. After 3 treatment cycles, her totalbody pain can decrease with each cycle of treatment, so that she can becurrently free of headaches, and body discomfort can be is limited tothe neck and jaw only. As a result of her residual discomfort the fourthtreatment can involve an increased dose and increased sites of Botulinumtreatment as follows: in addition to the above sites, the cervicalsensory rami can be treated by infiltrating the cervical paraspinalmuscles with 15 units on each side, and the masseter motor branches canbe treated with 15 units on each side. The total dose given can be 165units. She can no longer be on daily oral medications and her pain canhave resolved.

Example 6 Use of a Botulinum Toxin to Treat Central Post Stroke PainSyndrome

An 80 year old man with hypertension and diabetes can have a strokeinvolving the thalamus. Three months later, he can develop dysesthesias(a poorly localized burning sensation that can occur in his extremitiesafter a stimulus is applied), hyperpathia (a heightened response to apainful stimulus) and allodynia (a non painful stimulus is felt aspain). His condition may not improve with intra venous lidocaine andlarge amounts of oral opioids. Amitriptyline, Tegretol and Lamotriginecan also provide no benefit. He can be treated with a botulinum ToxinType A, 4 cc dilution, using the trigeminal targeting approach on oneoccasion. This can result in complete pain relief within 6 weeks oftreatment.

Example 7 Use of a Botulinum Toxin to Treat Regional Pain Syndrome

A 40 year old woman can develops reflex sympathetic dystrophy of theright lower extremity following a fall with a fractured fibular thatrequires surgically stabilization. A trial subcutaneous injection of abotulinum toxin type A along the painful dermatomes can provide no painrelief. The patient can complain of increased leg muscle fatigue afterthis treatment. She can have chronic renal failure and can be resistantto using oral treatments. A trigeminal targeting approach can beutilized using the protocol established in the above cases. Once again105 units can be injected. After 2 treatment cycles her pain candecrease to the point that she can once again start an exercise program.

Example 8 Use of a Botulinum Toxin to Treat Phantom Limb Pain

A 68 year old, diabetic woman can have had a left above knee amputationas a result of peripheral vascular disease. She can have severe residualleft foot pain which keeps her awake at night. She can have triedhypnosis without benefit. She can be on Pamelor and Neurontin and cannote mild benefit for sleep, but not pain. After two cycles of atrigeminal targeting of a botulinum toxin type A treatment she can beable to sleep through the night and can be in no discomfort.

Example 9 Use of a Botulinum Toxin to Treat Demyelinating Diseases

A 28 year old woman can have relapsing remitting multiple sclerosis andbe on Betaseron with relapses occurring about twice a year. She cantolerate the other MS immune modulating treatments poorly. She can havehad rheumatic fever as a child. Consequently, other available MSmodulating treatment may not be available to her. In desperation, abotulinum toxin type A, trigeminal targeting, can be used with thestandard 105 unit dose. After 4 cycles of treatment, she can have hadonly one relapse in the first month and her brain MRI scan can show noenhancing lesions.

Example 10 Use of a Botulinum Toxin to Treat a Bipolar Disorder

A female patient 24 years of age can experience rapid mood cycles fromdepression to euphoria which can require frequent admissions topsychiatric units and she is diagnosed with bipolar disorder. Thirtyunits of a botulinum toxin type can be administered subdermally aroundbranches of the trigeminal nerve and cervical plexus. Specifically, oneof more of the following locations can be administered (such as byinjection) the botulinum toxin: (1) the frontal branch of the ophthalmicdivision of the trigeminal nerve divides in the orbit into thesupratrochlear nerve and the supraorbital nerve. The supratrochlearnerve exits the orbit between the trochlea and the supraorbital foramen.The supraorbital nerve exits from the superior aspect of the orbitpassing through the supraorbital foramen. The supratrochlear andsupraorbital nerve branches of the trigeminal nerve can be localized foradministration of a botulinum toxin thereto by the supraorbital foramenor notch. Both of these nerves then travel under the frontalis muscleand above the periosteum. Thus, a botulinum toxin can be administeredbelow the frontalis muscle and above the periosteum to infiltrate theseperipheral branches (supratrochlear and supraorbital nerves) of thetrigeminal nerve. (2) The auriculotemporal branch of the trigeminalnerve arises from the mandibular division of the trigeminal nerve andexits in the region of the temporomandibular joint at which location thebotulinum toxin can be administered. (3) The superficial temporalbranches of the trigeminal nerve accompany the superficial temporalartery which is easily palpated for administration of a botulinum toxinalong its course. (4) The cervical rami of the trigeminal give rise tothe greater and lesser occipital nerves to which a botulinum toxin canbe administered at the location where they cross the nuchal ridge justmedial and lateral to the palpable occipital artery which lies midwaybetween the mastoid process and the inion. (5 The rami of the lowercervical nerves of the trigeminal nerve can be infiltrated with abotulinum toxin at the location where they penetrate the semispinalismuscle and trapezius muscle. Thus, administration of the botulinum toxincan be, for example, to one or more of these five trigeminal nervebranch sites. After treatment, the patients' bipolar condition canimprove within several weeks.

Example 11 Use of a Botulinum Toxin to Treat a Pain

The patient can be a woman in her 30's with reflex sympathetic dystrophyaffecting the right lower extremity status post an ankle fracture 5years earlier. The pain can be intractable to medical therapy includingbotulinum toxin type A injections to the painful dermatomes. Howeverfollowing botulinum toxin type A injections to the trigeminal andcervical plexus sensory branches (as set forth by Example 10), her paincan gradually diminish, and by the fourth, three monthly cycle, she canbe weaned off all medical treatments and can function normally.

Example 12 Use of a Botulinum Toxin to Treat a Epilepsy

The patient can be a 48 year old male with partial sensory seizures thatsecondarily generalize. He can have frequent generalized tonic clonicseizures with a poor response to medical treatment. Vagal nervestimulator (VNS) can be considered as this has been approved for partialonset seizures. The presumed mechanism of action of VNS is that corticalafferents can be down regulated via stimulation of the vagal nerve.However, VNS may worsen sleep apnea, and as this can be an issue in thispatient, VNS can be replaced by botulinum toxin type A injections aroundsensory branches of the trigeminal nerve and cervical plexus, as setforth in Example 10 above. After two treatment cycles, the patient'sseizures can be controlled with standard oral anticonvulsants for thefirst time. The injection technique used can involve branches of thetrigeminal nerve and cervical plexus such that cosmesis can be spared,i.e. lower facial and limb muscle strength can be preserved using thistechnique.

Example 13 Treatment of Schizophrenia with Botulinum Toxin Type A

A 48 year old male can present with reduced motivation and interest indaily life. The patient can indicate that he hears voices. The patientcan be monitored regularly for six months. The symptoms can graduallyworsen throughout the monitoring period, and the patient can bediagnosed with schizophrenia. Thirty units of a botulinum toxin type canbe administered subdermally around branches of the trigeminal nerve andcervical plexus, as set forth by Example 10. The patient can bedischarged within 48 hours and within a few (1-7) days can enjoy asignificant improvement of (relief from) the positive symptoms ofschizophrenia. The positive symptoms of schizophrenia can remainsignificantly alleviated for between about 2 to about 6 months. Forextended therapeutic relief, one or more polymeric implantsincorporating a suitable quantity of a botulinum toxin, such as abotulinum toxin type A can be placed at the target tissue site.

Example 14 Treatment of Schizophrenia With Botulinum Toxin Type B

A 68 year female previously diagnosed and treated for schizophrenia canwish to try a new therapeutic treatment. She can seek the advice of aphysician who can recommend botulinum toxin therapy. From 200 to about2000 units of a botulinum toxin type B preparation (such as Neurobloc®or Innervate™) can be administered to the pedunculopontine nuclei bysubdermal injection of the botulinum toxin around branches of thetrigeminal nerve and cervical plexus, as set forth by Example 10. Thepatient can be discharged within 48 hours and within a few (1-7) dayscan enjoy significant improvement of the positive symptoms ofschizophrenia. Her hallucinations can almost completely disappear. Thepositive symptoms can remain significantly alleviated for between about2 to about 6 months. For extended therapeutic relief, one or morepolymeric implants incorporating a suitable quantity of a botulinumtoxin type B can be placed at the target tissue site.

Example 15 Treatment of Schizophrenia with Botulinum Toxin Types C₁-G

A female aged 71 can be admitted with disordered thought patterns andsuffering from auditory and visual hallucinations. From 1 to 100 unitsof a botulinum toxin type C₁, D, E, F or G can be administered to thepedunculopontine nuclei, by subdermal injection around branches of thetrigeminal nerve and cervical plexus, as set forth by Example 10, tochemically denervate the excitatory cholinergic projection to theventral tegmental area. The patient can be discharged within about 48hours and with a few (1-7) days enjoys significant remission of allhallucinations which can remain significantly alleviated of the symptomsof schizophrenia for between about 2 to about 6 months. For extendedtherapeutic relief, one or more polymeric implants incorporating asuitable quantity of a botulinum toxin type C₁, D, E, F or G can beplaced at the target tissue site.

Example 16 Treatment of Alzheimer's Disease with Botulinum Toxin Type A

An 85 year old male who has experienced a progressive decline in mentalacuity and who no longer remembers how to perform simple tasks, such asbrushing teeth, or combing hair can be admitted. The patient can beotherwise healthy for an 85 year old. He can be diagnosed with advancedAlzheimer's disease. About thirty units of a botulinum toxin type A canbe administered to his locus coeruleus by subdermal injection of thebotulinum toxin around branches of the trigeminal nerve and cervicalplexus, as set forth by Example 10.

Although the patient's loss of memory may not recover fully, thepsychotic symptoms the patient was exhibiting can be reduced and canremain substantially alleviated for between about 2 months to about 6months per toxin injection or for between about 1 to 5 years dependingupon the particular release characteristics of the implant polymer andthe quantity of botulinum toxin loaded therein.

Example 17 Treatment of Alzheimer's Disease With Botulinum Toxin TypesB-G

The patient of Example 16 above can be equivalently treated using thesame protocol and, as set forth by Example 10 with between about 1 unitand about 1000 units of a botulinum toxin type B, C₁, D, E, F or G inaqueous solution or in the form of a suitable subdermal neurotoxinimplant. With such a treatment, the psychotic symptoms can subsidewithin 1-7 days, and can remain substantially alleviated for betweenabout 2-6 months per toxin injection or for between about 1 to 5 yearsdepending upon the particular release characteristics of the implantpolymer and the quantity of neurotoxin loaded therein.

Example 18 Treatment of Mania with Botulinum Toxin Type A

A 44 year old male can be diagnosed with mania. Thirty units of abotulinum toxin type A can be subdermally, non-intramuscularly injectedaround branches of the trigeminal nerve and cervical plexus, as setforth by Example 10. The patient's manic symptoms can subside within 1-7days, and can remain substantially alleviated for between about 2 monthsto about 6 months per toxin injection or for between about 1 to 5 yearsdepending upon the particular release characteristics of an implantpolymer which can be inserted and the quantity of the botulinum toxinloaded therein. Notably, there can be significant attenuation of themanic behavior and the patient has a substantially more controlledbehavioral pattern.

Example 19 Treatment of Mania with Botulinum Toxin Types B-G

The patient of example 18 above can be equivalently treated using thesame protocol and approach to target with between about 1 unit and about1000 units of a botulinum toxin type B, C₁, D, E, F or G in aqueoussolution or in the form of a suitable neurotoxin implant. With such atreatment, the symptoms can subside within 1-7 days, and can remainsubstantially alleviated for between about 2-6 months per toxininjection or for between about 1 to 5 years depending upon theparticular release characteristics of the implant polymer and thequantity of neurotoxin loaded therein. The implant can be implanted atone or more of the locations specified in Example 10.

Example 20 Treatment of Epilepsy with Botulinum Toxin Type A

A right handed, female patient age 22 can present with a history ofepilepsy. Based upon MRI and a study of EEG recording, a diagnosis oftemporal lobe epilepsy can be made. An implant which provides about 5-50units of a neurotoxin (such as a botulinum toxin type A) can be insertedsubdermally around branches of the trigeminal nerve and cervical plexus,as set forth by Example 10. The epileptic seizures can be substantiallyreduced within about two weeks, and can remain substantially alleviatedfor between about 2 months to about 6 months per toxin injection or forbetween about 1 to 5 years depending upon the particular releasecharacteristics of the implant polymer and the quantity of a botulinumtoxin loaded therein.

Example 21 Treatment of Epilepsy with Botulinum Toxin Types B-G

The patient of example 20 above can be equivalently treated using thesame protocol and approach to target with between about 1 unit and about1000 units of a botulinum toxin type B, C₁, D, E, F or G in aqueoussolution or in the form of a suitable neurotoxin implant. The implantcan be implanted at one or more of the locations specified in Example10. With such a treatment, the epileptic seizures can subside within 1-7days, and can remain substantially alleviated for between about 2-6months per toxin injection or for between about 1 to 5 years dependingupon the particular release characteristics of the implant polymer andthe quantity of neurotoxin loaded therein.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety. Allreferences, articles, patents, applications and publications set forthto above are incorporated herein by reference in their entireties.

I claim:
 1. A method for treating a social behavior disorder in apatient in need thereof, comprising administering a botulinum toxin to atrigeminal nerve of the patient, thereby treating the post-traumaticstress disorder.
 2. The method of claim 1, wherein the botulinum toxinis botulinum toxin type A.
 3. The method of claim 1, wherein thebotulinum toxin is botulinum toxin type B.
 4. The method of claim 1,wherein the method of local administration is injection.
 5. The methodof claim 1, wherein the administering is by non-intramuscular injection.6. The method of claim 1, wherein the administering is subdermal,intradermal or transdermal.
 7. The method of claim 1, wherein thetrigeminal nerve is selected from the group consisting of an ophthalmicnerve, maxillary nerve, mandibular nerve, supra orbital nerve, supratrochlear nerve, infraorbital nerve, lacrimal nerve, nasociliary nerve,superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolarnerve, mental nerve, an auriculotemporal nerve, lesser occipital nerveand a greater occipital nerve.
 8. The method of claim 1, wherein thesocial behavior disorder comprises character defects and personalitydisorders.
 9. A method for reducing the occurrence of a symptom ofsocial behavior disorder in a patient with social behaviour disorder,the method comprising locally administering a therapeutically effectiveamount of a botulinum toxin to a trigeminal sensory nerve or to thevicinity of a trigeminal sensory nerve of the patient, thereby reducingthe occurrence of a symptom of post-traumatic stress disorder, whereinthe administering is non-intramuscular.
 10. The method of claim 9,wherein the botulinum toxin is botulinum toxin type A.
 11. The method ofclaim 9, wherein the botulinum toxin is botulinum toxin type B.
 12. Themethod of claim 9, wherein the method of local administration isinjection.
 13. The method of claim 9, wherein the administering is bysubdermal, intradermal or transdermal.
 14. The method of claim 9,wherein the administering is subdermal.
 15. The method of claim 9,wherein the therapeutically effective amount of the botulinum toxinadministered is between about 1 unit and about 3,000 units.
 16. Themethod of claim 9, wherein the trigeminal sensory nerve is selected fromthe group consisting of an ophthalmic nerve, maxillary nerve, mandibularnerve, supra orbital nerve, supra trochlear nerve, infraorbital nerve,lacrimal nerve, nasociliary nerve, superior alveolar nerve, buccalnerve, lingual nerve, inferior alveolar nerve, mental nerve, anauriculotemporal nerve, lesser occipital nerve and a greater occipitalnerve.
 17. The method of claim 9, wherein the social behavior disordercomprises character defects and personality disorders.